Inhibitors of IMPDH enzyme

ABSTRACT

The present invention discloses the identification of the novel inhibitors of IMPDH (inosine-5′-monophosphate dehydrogenase). The compounds and pharmaceutical compositions disclosed herein are useful in treating or preventing IMPDH associated disorders, such as transplant rejection and autoimmune diseases.

This application is a Divisional of Ser. No. 09/427,953 filed Oct. 27,1999, now U.S. Pat. No. 6,624,184, which claims priority fromProvisional Ser. No. 60/106,180 filed Oct. 29, 1998.

FIELD OF THE INVENTION

The present invention relates to novel compounds which inhibit IMPDH.The invention also encompasses pharmaceutical compositions comprisingthese compounds. The compounds and pharmaceutical compositions of theinvention are particularly well suited for inhibiting IMPDH enzymeactivity and, consequently, may be advantageously used as therapeuticagents for IMPDH-associated dissorders. This invention also relates tomethods for inhibiting the activity of IMPDH using the compounds of thisinvention and related compounds.

BACKGROUND OF THE INVENTION

Inosine monophosphate dehydrogenase (IMPDH) has been shown to be a keyenzyme in the regulation of cell proliferation and differentiation.Nucleotides are required for cells to divide and replicate. In mammals,nucleotides may be synthesized through one of two pathways: the de novosynthesis pathway or the salvage pathway. The extent of utilization ofeach pathway is dependent on the cell type. This selectivity hasramifications with regard to therapeutic utility as described below.

IMPDH is involved in the de novo synthesis of guanosine nucleotides.IMPDH catalyzes the irreversible NAD-dependent oxidation ofinosine-5′-monophosphate (“IMP”) to xanthosine-5′-monophosphate (“XMP”),Jackson et al., Nature 256:331–333 (1975).

IMPDH is ubiquitous in eukaryotes, bacteria and protozoa. Theprokaryotic forms share 30–40% sequence identity with the human enzyme.

Two distinct cDNA's encoding IMPDH have been identified and isolated.These transcripts are labeled type I and type II and are of identicalsize (514 amino acids). Collart et al., J. Biol. Chem. 263:15769–15772(1988); Natsumeda et al., J. Biol. Chem. 265:5292–5295 (1990); and U.S.Pat. No. 5,665,583 to Collart et al. These isoforms share 84% sequenceidentity. IMPDH type I and type II form tetramers in solution, theenzymatically active unit.

B and T-lymphocytes depend on the de novo, rather than salvage pathway,to generate sufficient levels of nucleotides necessary to initiate aproliferative response to mitogen or antigen. Due to the B and T cell'sunique reliance on the de novo pathway, IMPDH is an attractive targetfor selectively inhibiting the immune system without also inhibiting theproliferation of other cells.

Immunosuppression has been achieved by inhibiting a variety of enzymes.Examples include: phosphatase calcineurin (inhibited by cyclosporin andFK-506); dihydroorotate dehydrogenase (DHODase), an enzyme involved inthe biosynthesis of pyrimidines (inhibited by leflunomide andbrequinar); the kinase FRAP (inhibited by rapamycin); and the heat shockprotein hsp70 (inhibited by deoxyspergualin).

Inhibitors of IMPDH have also been described in the art. WO 97/40028 andU.S. Pat. No. 5,807,876 describe a class of urea derivatives thatpossess a common urea backbone. A large number of compounds aredescribed in WO 97/40028 and U.S. Pat. No. 5,807,876, but several of thecompounds suffer from drawbacks such as inferior solubility. A recentpublication, WO 98/40381, describes a series of heterocyclic substitutedanilines as inhibitors of IMPDH.

U.S. Pat. Nos. 5,380,879 and 5,444,072 and PCT publications WO 94/01105and WO 94/12184 describe mycophenolic acid (“MPA”) and some of itsderivatives as potent, uncompetitive, reversible inhibitors of humanIMPDH type I and type II. MPA has been demonstrated to block theresponse of B and T-cells to mitogen or antigen. Immunosuppressants,such as MPA and derivatives of MPA, are useful drugs in the treatment oftransplant rejection and autoimmune disorders, psoriasis, inflammatorydiseases, including, rheumatoid arthritis, tumors and for the treatmentof allograft rejection. These are described in U.S. Pat. Nos. 4,686,234,4,725,622, 4,727,069, 4,753,935, 4,786,637, 4,808,592, 4,861,776,4,868,153, 4,948,793, 4,952,579, 4,959,387, 4,992,467; 5.247,083; andU.S. patent application Ser. No. 07/927,260, filed Aug. 7, 1992. MPAdoes display undesirable pharmacological properties, such asgastrointestinal toxicity and poor bioavailability.

Tiazofurin, ribavirin and mizoribine also inhibit IMPDH. Thesenucleoside analogs are competitive inhibitors of IMPDH, however theseagents inhibit other NAD dependent enzymes. This low level ofselectivity for IMPDH limits the therapeutic application of tiazofurin,ribavirin and mizoribine. Thus, new agents which have improvedselectivity for IMPDH would represent a significant improvement over thenucleoside analogs.

Mycophenolate mofetil, sold under the trade name CELLCEPT, is a prodrugwhich liberates MPA in vivo. It is approved for use in preventing acuterenal allograft rejection following kidney transplantation. The sideeffect profile limits the therapeutic potential of this drug. MPA israpidly metabolized to the inactive glucuronide in vivo. In humans, theblood levels of glucuronide exceed that of MPA. The glucuronideundergoes enterohepatic recycling causing accumulation of MPA in thebile and subsequently in the gastrointestinal tract. This together withthe production of the inactive glucuronide effectively lowers the drug'sin vivo potency, while increasing its undesirable gastrointestinal sideeffects.

Unlike type I, type II mRNA is preferentially upregulated in humanleukemic cell lines K562 and HL-60. Weber, J. Biol. Chem. 266: 506–509(1991). In addition, cells from human ovarian tumors and leukemic cellsfrom patients with chronic granulocytic, lymphocytic and acute myeloidleukemias also display an up regulation type II mRNA. Thisdisproportionate increase in IMPDH activity in malignant cells may beaddressed through the use of an appropriate IMPDH inhibitor. IMPDH hasalso been shown to play a role in the proliferation of smooth musclecells, indicating that inhibitors of IMPDH may be useful in preventingrestenosis or other hyperproliferative vascular diseases.

IMPDH has been shown to play a role in viral replication in some viralcell lines. Carr, J. Biol. Chem. 268:27286–27290 (1993). The IMPDHinhibitor VX-497, is currently being evaluated for the treatment ofhepatitis C virus in humans. Ribavirin has also been used in thetreatment of hepatitis C and B viruses and when used in combination withinterferon an enhancement in activity was observed. The IMPDH inhibitorribavirin is limited by its lack of a sustained response in monotherapyand broad cellular toxicity.

There remains a need for potent selective inhibitors of IMPDH withimproved pharmacological properties, physical properties and fewer sideeffects. Such inhibitors would have therapeutic potential asimmunosuppressants, anti-cancer agents, anti-vascular hyperproliferativeagents, antiinflammatory agents, antifungal agents, antipsoriatic andanti-viral agents. The compounds of the present invention differ fromthose taught by the prior art and are effective inhibitors of IMPDH.

SUMMARY OF THE INVENTION

The present invention provides compounds of the following formula I,stereoisomeric forms thereof, tautomeric forms thereof, pharmaceuticallyacceptable salt forms thereof, or prodrug forms thereof, for use asinhibitors of IMPDH enzyme:

wherein:

Z is a monocyclic or bicyclic ring system optionally containing up to 4heteroatoms selected from N, O, and S, and wherein a CH₂ adjacent to anyof the said N, O or S heteroatoms is optionally substituted with oxo(═O), and wherein Z is optionally substituted with 0–5 substituentschosen from R¹, R², R³ or R⁴;

R¹ and R² are each independently selected from the group consisting ofH, F, Cl, Br, I, NO₂, CF₃, CN, OCF₃, OH, C₁–C₄alkoxy-,C₁–C₄alkylcarbonyl-, C₁–C₆alkyl, hydroxy C₁–C₄ alkyl-, C₃–C₆ alkenyl,C₃–C₆ alkynyl, C₃–C₁₀ cycloalkyl(C₀–C₄alkyl)-, H₂N(C₀–C₄)alkyl-,R⁶HN(C₀–C₄)alkyl-, R⁶R⁷N(C₀–C₄)aIkyl-, R⁷S(C₀–C₄)alkyl-,R⁷S(O)(C₀–C₄)alkyl-, R⁷SO₂(C₀–C₄)alkyl-, R⁶R⁷NSO₂(C₀–C₄)alkyl-, HSO₃,HO₂C(C₀–C₄)alkyl-, R⁶O₂C(C₀–C₄)alkyl-, and R⁶R⁷NCO(C₀–C₄)alkyl-, oralternatively, R¹ and R², when on adjacent carbon atoms, and when takentogether are methylenedioxy or ethylenedioxy,

R³ is a 5- or 6-membered heterocyclic ring system containing up to 4heteroatoms selected from N, O, and S, said heterocyclic ring systembeing optionally substituted with 0–3 R⁵, wherein when R⁵ is hydroxy theheterocycle may undergo tautomerization to an oxo species or may existas an equilibrium mixture of both tautomers;

R⁴ is selected from F, Cl, Br, I, NO₂, CF₃, CN, C₁-C₄alkoxy-, OH, oxo,CF₃O, haloalkyloxy, C₀–C₄ alkylhydroxy, C₁–C₄ alkyl-,C₁–C₄alkylcarbonyl-, C₀–C₄ alkylOCOR⁶, C₀–C₄ alkylOC(═O)OR⁶, C₀–C₄alkylOC(═O)NR⁶R⁷, NH₂, NHR⁶, C₀–C₄ alkylNR⁶R⁷, C₀–C₄ alkylNR⁷C(═O)OR⁶,C₀–C₄ alkylNR⁶SO₂NR⁶R⁷, C₀–C₄ alkylNR⁷SO₂R⁶, C₀–C₄ alkylSR⁶, C₀–C₄alkylS(O)R⁶, C₀–C₄ alkylSO₂R⁶, SO₃R⁷, C₀–C₄alkylSO₂NR⁶R⁷, C₀–C₄alkylSO₂NR⁷CO(CR⁹R¹⁰)₀₋₃R⁶, C₀–C₄ alkylCO₂H, C₀–C₄ alkylCO₂R⁶, C₀–C₄alkylCONR⁶R⁷, and C₀–C₄alkylCONR⁷SO₂(CR⁹R¹⁰)₀₋₃R⁶;

R⁵ is selected from the group consisting of H, C₁–C₄ alkyl, C₃–C₇cycloalkyl, F, Cl, Br, I, NO₂, CN, CF₃, OCF₃, OH, oxo, C₁–C₄alkoxy-,hydroxyC₁–C₄ alkyl-, C₁–C₄ alkylcarbonyl-, CO₂H, CO₂R⁶, CONR⁶R⁷, NHR⁶,and NR⁶R⁷;

R⁶ is selected from the group consisting of H, C₁–C₈ alkyl, C₃–C₆alkenyl, C₃–C₆ alkynyl, C₃–C₁₀ cycloalkyl(C₀–C₄ alkyl)-, aryl(C₀–C₄alkyl)-, and heterocyclic (C₀–C₄ alkyl)-,

wherein said aryl or heterocyclic groups are substituted with 0–2substituents independently selected from the group consisting of C₁–C₄alkyl, C₁–C₄ alkoxy, hydroxy C₀–C₄ alkyl, oxo, F, Cl, Br, CF₃, NO₂, CN,OCF₃, NH₂, NHR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₂NR⁷R⁸, CO₂H, CO₂R⁷, andCONR⁷R⁸;

R⁷ and R⁸ are each independently selected from the group consisting ofH, C₁–C₈ alkyl, C₃–C₆ alkenyl, C₃–C₆ alkynyl, C₃–C₁₀ cycloalkyl(C₀–C₄alky)-, C₁C₆ alkylcarbonyl, C₃–C₇ cycloalkyl(C₀–C₅ alkyl)carbonyl, C₁–C₆alkoxycarbonyl, C₃–C₇ cycloalkyl(C₀–C₅ alkoxy)carbonyl, aryl(C₁–C₅alkoxy)carbonyl, arylsulfonyl, aryl(C₀–C₄ alkyl)-, heterocyclic(C₁–C₅alkoxy)carbonyl, heterocyclic sulfonyl and heterocyclic (C₀–C₄ alkyl)-,wherein said aryl or heterocyclic groups are substituted with 0–2substituents independently selected from the group consisting of C₁–C₄alkyl, C₁–C₄ alkoxy, F, Cl, Br, CF₃, CN, and NO₂;

alternatively, R⁶ and R⁷, or R⁶ and R⁸, or R⁷ and R⁸, when bothsubstituents are on the same nitrogen atom [as in (—NR⁶R⁷) or (—NR⁷R⁸)],can be taken together with the nitrogen atom to which they are attachedto form a heterocycle selected from the group consisting of1-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl,1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl, saidheterocycle being optionally substituted with 0–3 groups selected fromthe group consisting of oxo, C₁–C₆ alkyl, C₃–C₇ cycloalkyl(C₀–C₄alkyl)-, C₁–C₆ alkylcarbonyl, C₃–C₇ cycloalkyl(C₀–C₅ alkyl)carbonyl,C₁–C₆ alkoxycarbonyl, C₃–C₇ cycloalkyl(C₀–C₅ alkoxy)carbonyl, aryl(C₀–C₅alkyl), heterocyclic(C₀–C₅ alkyl), aryl(C₁–C₅ alkoxy)carbonyl,heterocyclic(C₁–C₅ alkoxy)carbonyl, C₁–C₆ alkylsulfonyl, arylsulfonyl,and heterocyclicsulfonyl,

wherein said aryl or heterocyclic groups are substituted with 0–2substituents independently selected from the group consisting of C₁–C₄alkyl, C₁–C₄ alkoxy, F, Cl, Br, CF₃, CN, and NO₂;

J is selected from the group consisting of —NR⁷— and —C(═O)—;

K is selected from the group consisting of —NR⁷—, —C(═O)—, and —CHR⁹—;

L is selected from the group consisting of a single bond, —C(═O),—CR¹⁰R¹¹—, —C(═O)CR¹⁰R¹¹—, —CR¹⁰R¹¹C(═O)—, —CR¹⁰R¹¹C(═O)—,—HR¹⁵C—CHR¹⁶—, and —R¹⁵C═CR¹⁶;

R⁹ is selected from the group consisting of H, C₁–C₈ alkyl, C₃–C₆alkenyl, C₃–C₁₀ cycloalkyl(C₀–C₄ alkyl)-, aryl(C₀–C₄ alkyl)-, andheterocyclic(C₀–C₄ alkyl)-,

wherein said aryl or heterocyclic groups are substituted with 0–2substituents independently selected from the group consisting of C₁–C₄alkyl, C₁–C₄ alkoxy, F, Cl, Br, CF₃, and NO₂;

R¹⁰ is selected from the group consisting of H, F, Cl, Br, C₁–C₆ alkoxy,C₁–C₈ alkyl, C₃–C₆ alkenyl, C₃–C₁₀ cycloalkyl(C₀–C₄ alkyl)-, aryl(C₀–C₄alkyl)-, and heterocyclic(C₀–C₄ alkyl)-, wherein said aryl orheterocyclic groups are substituted with 0–2 substituents independentlyselected from the group consisting of C₁–C₄ alkyl, C₁–C₄ alkoxy, F, Cl,Br, CF₃, CN, and NO₂;

R¹¹ is selected from the group consisting of H, F, Cl, Br, OMe, C₁–C₈alkyl, C₃–C₆ alkenyl, C₃–C₁₀ cycloalkyl(C₀–C₄ alkyl)-, aryl(C₀–C₄alkyl)-, and heterocyclic(C₀–C₄ alkyl)-, wherein said aryl orheterocyclic groups are substituted with 0–2 substituents independentlyselected from the group consisting of C₁–C₄ alkyl, C₁–C₄ alkoxy, F, Cl,Br, CF₃, CN, and NO₂;

alternatively, R¹⁰ and R¹¹, when on the same carbon atom [as in(—CR¹⁰R¹¹—)], can be taken together with the carbon atoms to which theyare attached to form a 3–7 membered carbocyclic or 3–7 memberedheterocyclic non-aromatic ring system, said carbocyclic or heterocyclicring being optionally substituted with 0–2 substituents independentlyselected from the group consisting of C₁–C₄ alkyl, C₁–C₄ alkoxy, hydroxyC₀–C₄ alkyl, oxo, F, Cl, Br, CF₃, and NO₂;

X is selected from the group consisting of OR¹², NR¹²R¹³, C₁–C₈ alkyl,C₃–C₆ alkenyl, C₃–C₁₀ cycloalkyl(C₀–C₄ alkyl)-, C₆–C₁₀ aryl(C₀–C₄alkyl)-, and heterocyclic(C₀–C₄ alkyl)-,

wherein said aryl or heterocyclic groups are substituted with 0–3substituents independently selected from R¹⁴, with the proviso that whenL is a single bond, X cannot be NR¹²R¹³;

R¹² is selected from the group consisting of H, C₁–C₈ alkyl, C₃–C₆alkenyl, C₃–C₁₀ cycloalkyl(C₀–C₄ alkyl)-, monocyclic or bicyclicaryl(C₀–C₄ alkyl)-, and monocyclic or bicyclic 5–10 memberedheterocyclic(C₀–C₄ alkyl)-, and —CZ¹Z²Z³,

wherein said aryl or heterocyclic groups are substituted with 0–3substituents independently selected from R¹⁴;

Z¹ is selected from the group consisting of C₁–C₈ alkyl, C₂–C₆ alkenyl,C₂–C₆ alkynyl, C₁-C₆ hydroxyalkyl, C₁-C₄ alkoxy C₁-C₄ alkyl, aryl(C₀-C₄alkyl)-, and 4–10 membered heterocyclic (C₀–C₄ alkyl)-,

wherein said aryl or heterocyclic groups are substituted with 0–3substituents independently selected from R¹⁴;

Z² is selected from the group consisting of C₁–C₈ alkyl, C₂–C₆ alkenyl,C₂–C₆ alkynyl, C₁–C₆ hydroxyalkyl, C₁–C₄ alkoxy C₁–C₄ alkyl, C₁–C₆NR¹⁷R¹⁸, aryl(C₀–C₄alkyl)-, and 4–10 membered heterocyclic (C₀–C₄alkyl)-,

wherein said aryl or heterocyclic groups are substituted with 0–3substituents independently selected from R¹⁴;

Z³ is selected from the group consisting of C₁–C₈ alkyl, R¹⁴(C₂–C₄alkyl)-, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ hydroxyalkyl, C₁–C₄ alkoxyC₁–C₄ alkyl, aryl(C₀–C₄ alkyl)-, 4–10 membered heterocyclic (C₀–C₄alkyl)-, R¹⁷O═C(C₀–C₄ alkyl)-, R¹⁷OO═C(C₀–C₄ alkyl)-, andR¹⁷R¹⁸NO═C(C₀–C₄ alkyl)-,

wherein said aryl or heterocyclic groups are substituted with 0–3substituents independently selected from R¹⁴;

alternatively, Z¹ and Z², when on the same carbon atom [as in(—CZ¹Z²—)], can be taken together with the carbon atoms to which theyare attached to form a 3–7 membered carbocyclic or 3–7 memberedheterocyclic non-aromatic ring system, said carbocyclic or heterocyclicring being optionally substituted with 0–2 substituents independentlyselected from R¹⁴.

R¹³ is selected from the group consisting of H, C₁–C₈ alkyl, C₃–C₆alkenyl, C₃–C₁₀ cycloalkyl(C₀–C₄ alkyl)-, C₁–C₆ alkylcarbonyl, C₁–C₆alkylsulfonyl, C₃–C₇ cycloalkyl(C₀–C₅ alkyl)carbonyl, C₁–C₆alkoxycarbonyl, C₃–C₇ cycloalkyl(C₀–C₅ alkoxy)carbonyl, aryl(C₀–C₄alkyl)-, aryl(C₁–C₅ alkoxy)carbonyl, arylsulfonyl, heterocyclic(C₀–C₄alkyl), heterocyclic(C₁–C₅ alkoxy)carbonyl, and heterocyclicsulfonyl,

wherein said aryl or heterocyclic groups are substituted with 0–2substituents independently selected from the group consisting of C₁–C₄alkyl, C₁–C₄ alkoxy, F, Cl, Br, CF₃, CN, and NO₂;

alternatively, R¹² and R¹³, when both are on the same nitrogen atom [asin (—NR¹²R¹³)] can be taken together with the nitrogen atom to whichthey are attached to form a heterocycle selected from 1-aziridinyl,1-azetidinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl,thiamorpholinyl, thiazolidinyl, and 1-piperazinyl,

said heterocycle being optionally substituted with 0–3 groupsindependently selected from oxo, C₁–C₆ alkyl, C₃–C₇ cycloalkyl(C₀–C₄alkyl)-, C₁–C₆ alkylcarbonyl, C₃–C₇ cycloalkyl(C₀–C₅ alkyl)carbonyl,C₁–C₆ alkoxycarbonyl, C₃–C₇ cycloalkyl(C₀–C₅ alkoxy)carbonyl, aryl(C₀–C₅alkyl), heterocyclic(C₀–C₅ alkyl), aryl(C₁–C₅ alkoxy)carbonyl,heterocyclic(C₁–C₅ alkoxy)carbonyl, C₁–C₆ alkylsulfonyl arylsulfonyl andheterocyclicsulfonyl,

wherein said aryl or heterocyclic groups are substituted with 0–2substituents independently selected from the group consisting of CH₃—,alkoxy, F, Cl, Br, CF₃, CN, and NO₂;

R¹⁴ is selected from the group consisting of H, C₁–C₁₀ alkyl, NO₂, CF₃,CN, F, Cl, Br, C₁–C₁₀ alkylcarbonyl, haloalkyl, haloalkoxy, OH,NR⁶R⁷(C₀–C₄ alkyl)-, R⁶C(═O)O(C₀–C₄ alkyl)-, R⁶C(═O)O(C₀–C₄ alkyl)-,R⁶O(C₀–C₄ alkyl), R⁶R⁷NC(═O) O(C₀–C₄ alkyl)-, R⁶R⁷NC(═O)(C₀–C₄ alkyl)-,R⁶O(CR¹⁰R¹¹)₂₋₆R⁶NC(═O)(C_(0–C) ₄ alkyl)-,R⁶R⁷N(CR¹⁰R¹¹)₂₋₆R⁶NC(═O)(C₀–C₄ alkyl)-, R⁶O₂C(CH₂)₁₋₄O(C₀–C₄alkyl)-,R⁶OOC(C₁–C₄ alkoxy)-, R⁶OOC(C₀–C₄ alkyl)-, R⁶C(═O)(C₀–C₄ alkyl)-,R⁶C(═O)NR⁷(C₀–C₄ alkyl)-, R⁶OC(═O)NR⁷(C₀–C₄ alkyl)-, R⁶OC(═NCN)NR⁷(C₀–C₄alkyl)-, R⁶R⁷NC(═O)NR⁸(C₀–C₄ alkyl)-, R⁶OC(═NC)NR⁷(C₀–C₄ alkyl)-,R⁶(CR¹⁰R¹¹)₁₋₄ NR⁷C═O—, R⁶O(CR¹⁰R¹¹)₁₋₄O═CR⁷N—, NR⁶R⁷(CR¹⁰R¹¹)₁₋₄C═OR⁷N—, R⁶O(CR¹⁰R¹¹)₂₋₄R⁷N—, R⁶O₂C(CR¹⁰R¹¹)₁₋₄R⁷N, R⁶R⁷N(CR¹⁰R¹¹)₂₋₄R⁷N—,R⁶R⁷NC(═NCN)NR⁷(C₀–C₄ alkyl)-, R⁶R⁷NC(═C(H)(NO₂))NR⁷(C₀–C₄ alkyl)-,R⁷R⁸NC (═NR⁷)NR⁷(C₀–C₄ alkyl)-, R⁶R⁷NSO₂NR⁸(C₀–C₄ alkyl)-,R⁶SO₂NR⁷(C₀–C₄alkyl)-, R⁶R⁷N(C₁–C₄)CO—, R⁶R⁷N(C₂–C₆ alkyl)O—,R⁶CO(CR¹⁰R¹¹)₀₋₂R⁷N(O₂)S(C₀–C₄ alkyl), R⁶(O₂)SR⁷NC(═O)(C₀–C₄ alkyl)-,R⁶S(C₀–C₄ alkyl)-, R⁶S(═O)(C₀–C₄ alkyl)-, R⁶SO₂(C₀–C₄ alkyl)-, SO₂NR⁶R⁷,SiMe₃, R⁶RN(C₂–C₄ alkyl)-, R⁶R⁷N(C₂–C₄ alkyl)-, HSO₃, HONH—, R⁶ONH—,R⁸R⁷NNR⁶—, HO(COR⁶)N—, HO(R⁶O₂C)N, C₂–C₆ alkenyl, C₃–C₁₀ cycloalkyl,C₃–C₁₀ cycloalkylmethyl, aryl(C₀–C₄alkyl)-, heteroaryl(C₀–C₄alkyl)-,aryl(C₀–C₄alkyl)O—, and heteroaryl(C₀–C₄alkyl)O—,

wherein said aryl groups are substituted with 0–2 substituentsindependently selected from a group consisting of C₁–C₄ alkyl, C₁–C₄alkoxy, F, Cl, Br, CF₃, and NO₂;

R¹⁵ is selected from the group consisting of H, halo, cyano, C₁–C₈alkyl, C₃–C₆ alkenyl, and C₃–C₁₀ cycloalkyl(C₀–C₄ alkyl)-, aryl(C₀–C₄alkyl)-, and heterocyclic(C₀–C₄ alkyl)-,

wherein said aryl or heterocyclic groups are substituted with 0–2substituents independently selected from R¹⁴;

R¹⁶ is selected from the group consisting of H, halo, cyano, C₁–C₈alkyl, C₃–C₆ alkenyl, C₃–C₁₀ cycloalkyl(C₀–C₄ alkyl)-, aryl(C₀-C₄alkyl)-, and heterocyclic(C₀–C₄ alkyl)-,

wherein said aryl or heterocyclic groups are substituted with 0–2substituents independently selected from R¹⁴;

alternatively, when R¹⁵ and R¹⁶ are on adjacent carbon atoms [as in—HR¹⁵C—CHR¹⁶—], or when R¹⁵ and R¹⁶ are oriented on the same side of thedouble bond [as in the following structure (III)

R¹⁵ and R¹⁶ can be taken together with the carbon atoms to which theyare attached to form a 3–7 membered carbocyclic aromatic or nonaromaticring system, or a 3–7 membered heterocyclic aromatic or nonaromatic ringsystem, said carbocyclic or heterocyclic ring being optionallysubstituted with 0–2 substituents independently selected from the groupconsisting of C₁–C₄ alkyl, C₁–C₄ alkoxy, F, Cl, Br, CF₃, NO₂;

R¹⁷ is selected from the group consisting of H, C₁–C₈ alkyl, C₃–C₆alkenyl, C₃–C₁₀ cycloalkyl(C₀–C₄ alkyl)-, C₁–C₆ alkylcarbonyl, C₁–C₆alkylsulfonyl, C₃–C₇ cycloalkyl(C₀–C₅ alkyl)carbonyl, C₁–C₆alkoxycarbonyl, C₃–C₇ cycloalkyl(C₀–C₅ alkoxy)carbonyl,hydroxy(C₂–C₄)alkyl-, C₁–C₃ alkoxy(C₂–C₄)alkyl-, (C₀–C₄ alkyl) (C₀–C₄alkyl) amino(C₂–C₄)alkyl-, aryl(C₀–C₄ alkyl)-, aryl(C₁–C₅alkoxy)carbonyl, arylsulfonyl, heterocyclic(C₀–C₄ alkyl),heterocyclic(C₁–C₅ alkoxy)carbonyl, and heterocyclicsulfonyl,

wherein said aryl or heterocyclic groups are substituted with 0–2substituents independently selected from the group consisting of C₁–C₄alkyl, C₁–C₄ alkoxy, C₁–C₄ alkoxy C₁–C₄ alkyl, oxo, F, Cl, Br, CF₃, CN,and NO₂;

R¹⁸ is selected from the group consisting of H, C₁–C₈ alkyl, C₃–C₆alkenyl, C₃–C₁₀ cycloalkyl(C₀–C₄ alkyl)-, aryl(C₀–C₄ alkyl)-, andheterocyclic(C₀–C₄ alkyl),

wherein said aryl or heterocyclic groups are substituted with 0–2substituents independently selected from the group consisting of C₁–C₄alkyl, C₁–C₄ alkoxy, F, Cl, Br, CF₃, CN, and NO₂; and

alternatively, R¹⁷ and R¹⁸, when both are on the same nitrogen atom [asin (—NR¹²R¹³)] can be taken together with the nitrogen atom to whichthey are attached to form a heterocycle selected from 1-aziridinyl,1-azetidinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl,thiamorpholinyl, thiazolidinyl, and 1-piperazinyl,

said heterocycle being optionally substituted with 0–3 groups selectedfrom oxo, C₁–C₆ alkyl, C₃–C₇ cycloalkyl(C₀–C₄ alkyl)-, C₁–C₆alkylcarbonyl, (C₀–C₆ alkylcarbonyl)(C₀–C₄alkyl)amino-, C₃–C₇cycloalkyl(C₀–C₅ alkyl)carbonyl, C₁–C₆ alkoxycarbonyl, C₃–C₇cycloalkyl(C₀–C₅ alkoxy)carbonyl, aryl(C₀–C₅ alkyl), heterocyclic(C₀–C₅alkyl), aryl(C₁–C₅ alkoxy)carbonyl, heterocyclic(C₁–C₅ alkoxy)carbonyl,C₁–C₆ alkylsulfonyl arylsulfonyl and heterocyclicsulfonyl,

wherein said aryl or heterocyclic groups are substituted with 0–2substituents independently selected from the group consisting of CH₃—,alkoxy, F, Cl, Br, CF₃, CN, and NO₂.

Compounds of formula I, their enantiomers, diasteromers, tautomers andpharmaceutically acceptable salts, prodrugs and solvates thereof, arenovel.

The present invention also provides pharmaceutical compositionscomprising the compounds of formula I and methods of treatingIMPDH-associated disorders using the compounds of formula I.

The compounds of the present invention offer therapeutic advantages overknown prior art compounds, and are useful in treating IMPDH-associateddisorders. These advantages include increased solubility (which in turnincreases overall therapeutic benefit) and reduction in negative sideeffects.

DETAILED DESCRIPTION OF THE INVENTION

As described above, the present invention encompasses compounds of thefollowing formula I, stereoisomeric forms thereof, tautomeric formsthereof, pharmaceutically acceptable salt forms thereof, or prodrugforms thereof:

wherein:

Z is a monocyclic or bicyclic ring system optionally containing up to 4heteroatoms selected from N, O, and S, and wherein a CH₂ adjacent to anyof the said N, O or S heteroatoms is optionally substituted with oxo(═O), and wherein Z is optionally substituted with 0–5 substituentschosen from R¹, R², R³ or R⁴;

R¹ and R² are each independently selected from the group consisting ofH, F, Cl, Br, I, NO₂, CF₃, CN, OCF₃, OH, C₁–C₄alkoxy-,C₁–C₄alkylcarbonyl-, C₁–C₆alkyl, hydroxy C₁–C₄ alkyl-, C₃–C₆ alkenyl,C₃–C₆ alkynyl, C₃–C₁₀ cycloalkyl(C₀–C₄alkyl)-, H₂N(C₀–C₄)alkyl-,R⁶HN(C₀–C₄)alkyl-, R⁶R⁷N(C₀–C₄)aIkyl-, R⁷S(C₀–C₄)alkyl-,R⁷S(O)(C₀–C₄)alkyl-, R⁷SO₂(C₀–C₄)alkyl-, R⁶R⁷NSO₂(C₀–C₄)alkyl-, HSO₃,HO₂C(C₀–C₄)alkyl-, R⁶O₂C(C₀–C₄)alkyl-, and R⁶R⁷NCO(C₀–C₄)alkyl-, oralternatively, R¹ and R², when on adjacent carbon atoms, and when takentogether are methylenedioxy or ethylenedioxy,

R³ is a 5- or 6-membered heterocyclic ring system containing up to 4heteroatoms selected from N, O, and S, said heterocyclic ring systembeing optionally substituted with 0–3 R⁵, wherein when R⁵ is hydroxy theheterocycle may undergo tautomerization to an oxo species or may existas an equilibrium mixture of both tautomers;

R⁴ is selected from F, Cl, Br, I, NO₂, CF₃, CN, C₁–C₄alkoxy-, OH, oxo,CF₃O, haloalkyloxy, C₀–C₄alkylhydroxy, C₁–C₄alkyl-, C₁–C₄alkylcarbonyl-,C₀–C₄alkylOCOR⁶, C₀–C₄alkylOC(═O)OR⁶, C₀–C₄ alkylOC(═O)NR⁶R⁷, NH₂, NHR⁶,C₀–C₄alkylNR⁶R⁷, C₀–C₄alkylNR⁶C(═O)OR⁶, C₀–C₄ alkylNR⁶SO₂NR⁶R⁷,C₀–C₄alkylNR⁷SO₂R⁶, C₀–C₄alkylSR⁶, C₀–C₄alkylS(O)R⁶, C₀–C₄alkylSO₂R⁶,SO₃R⁷, C₀–C₄ alkylSO₂NR⁶R⁷, C₀–C₄alkylSO₂NR⁷CO(CR⁹R¹⁰)₀₋₃R⁶,C₀–C₄alkylCO₂H, C₀–C₄alkylCO₂R⁶, C₀–C₄alkylCONR⁶R⁷, andC₀–C₄alkylCONR⁷SO₂(CR⁹R¹⁰)₀₋₃R⁶;

R⁵ is selected from the group consisting of H, C₁–C₄ alkyl, C₃–C₇cycloalkyl, F, Cl, Br, I, NO₂, CN, CF₃, OCF₃, OH, oxo, C₁–C₄alkoxy-,hydroxyC₁–C₄ alkyl-, C₁–C₄ alkyl-, C₁–C₄ alkylcarbonyl-, CO₂H, CO₂R⁶,CONR⁶R⁷, NHR⁶, and NR⁶R⁷;

R⁶ is selected from the group consisting of H, C₁–C₈ alkyl, C₃–C₆alkenyl, C₃–C₆ alkynyl, C₃–C₁₀ cycloalkyl(C₀–C₄ alkyl)-, aryl(C₀–C₄alkyl)-, and heterocyclic (C₀–C₄ alkyl)-,

wherein said aryl or heterocyclic groups are substituted with 0–2substituents independently selected from the group consisting of C₁–C₄alkyl, C₁–C₄ alkoxy, hydroxy C₀–C₄ alkyl, oxo, F, Cl, Br, CF₃, NO₂, CN,OCF₃, NH₂, NHR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₂NR⁷R⁸, CO₂H, CO₂R⁷, andCONR⁷R⁸;

R⁷ and R⁸ are each independently selected from the group consisting ofH, C₁–C₈ alkyl, C₃–C₆ alkenyl, C₃–C₆ alkynyl, C₃–C₁₀ cycloalkyl(C₀–C₄alkyl)-, C₁–C₆ alkylcarbonyl, C₃–C₇ cycloalkyl(C₀–C₅ alkyl)carbonyl,C₁–C₆ alkoxycarbonyl, C₃–C₇ cycloalkyl(C₀–C₅ alkoxy)carbonyl, aryl(C₁–C₅alkoxy)carbonyl, arylsulfonyl, aryl(C₀–C₄ alkyl)-, heterocyclic(C₁–C₅alkoxy)carbonyl, heterocyclic sulfonyl and heterocyclic (C₀–C₄ alkyl)-,wherein said aryl or heterocyclic groups are substituted with 0–2substituents independently selected from the group consisting of C₁–C₄alkyl, C₁–C₄ alkoxy, F, Cl, Br, CF₃, CN, and NO₂;

alternatively, R⁶ and R⁷, or R⁶ and R⁸, or R⁷ and R⁸, when bothsubstituents are on the same nitrogen atom [as in (—NR⁶R⁷) or (—NR⁷R⁸)],can be taken together with the nitrogen atom to which they are attachedto form a heterocycle selected from the group consisting of1-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl,1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl, saidheterocycle being optionally substituted with 0–3 groups selected fromthe group consisting of oxo, C₁–C₆ alkyl, C₃–C₇ cycloalkyl(C₀–C₄alkyl)-, C₁–C₆ alkylcarbonyl, C₃–C₇ cycloalkyl(C₀–C₅ alkyl)carbonyl,C₁–C₆ alkoxycarbonyl, C₃–C₇ cycloalkyl(C₀–C₅ alkoxy)carbonyl, aryl(C₀–C₅alkyl), heterocyclic(C₀–C₅ alkyl), aryl(C₁–C₅ alkoxy)carbonyl,heterocyclic(C₁–C₅ alkoxy)carbonyl, C₁–C₆ alkylsulfonyl, arylsulfonyl,and heterocyclicsulfonyl,

wherein said aryl or heterocyclic groups are substituted with 0–2substituents independently selected from the group consisting of C₁–C₄alkyl, C₁–C₄ alkoxy, F, Cl, Br, CF₃, CN, and NO₂;

J is selected from the group consisting of —NR⁷— and —C(═O)—;

K is selected from the group consisting of —NR⁷—, —C(═O)—, and —CHR⁹—;

L is selected from the group consisting of a single bond, —C(═O),—CR¹⁰R¹¹—, —C(═O)CR¹⁰R¹¹—, —CR¹⁰R¹¹C(═O)—, —CR¹⁰R¹¹C(═O)—,—HR¹⁵C—CHR¹⁶—, and —R¹⁵C═CR¹⁶;

R⁹ is selected from the group consisting of H, C₁–C₈ alkyl, C₃–C₆alkenyl, C₃–C₁₀ cycloalkyl(C₀–C₄ alkyl)-, aryl(C₀–C₄ alkyl)-, andheterocyclic(C₀–C₄ alkyl)-,

wherein said aryl or heterocyclic groups are substituted with 0–2substituents independently selected from the group consisting of C₁–C₄alkyl, C₁–C₄ alkoxy, F, Cl, Br, CF₃, and NO₂;

R¹⁰ is selected from the group consisting of H, F, Cl, Br, C₁–C₆ alkoxy,C₁–C₈ alkyl, C₃–C₆ alkenyl, C₃–C₁₀ cycloalkyl(C₀–C₄ alkyl)-, aryl(C₀–C₄alkyl)-, and heterocyclic(C₀–C₄ alkyl)-, wherein said aryl orheterocyclic groups are substituted with 0–2 substituents independentlyselected from the group consisting of C₁–C₄ alkyl, C₁–C₄ alkoxy, F, Cl,Br, CF₃, CN, and NO₂;

R¹¹ is selected from the group consisting of H, F, Cl, Br, OMe, C₁–C₈alkyl, C₃–C₆ alkenyl, C₃–C₁₀ cycloalkyl(C₀–C₄ alkyl)-, aryl(C₀–C₄alkyl)-, and heterocyclic(C₀–C₄ alkyl)-, wherein said aryl orheterocyclic groups are substituted with 0–2 substituents independentlyselected from the group consisting of C₁–C₄ alkyl, C₁–C₄ alkoxy, F, Cl,Br, CF₃, CN, and NO₂;

alternatively, R¹⁰ and R¹¹, when on the same carbon atom [as in(—CR¹⁰R¹¹—)], can be taken together with the carbon atoms to which theyare attached to form a 3–7 membered carbocyclic or 3–7 memberedheterocyclic non-aromatic ring system, said carbocyclic or heterocyclicring being optionally substituted with 0–2 substituents independentlyselected from the group consisting of C₁–C₄ alkyl, C₁–C₄ alkoxy, hydroxyC₀–C₄ alkyl, oxo, F, Cl, Br, CF₃, and NO₂;

X is selected from the group consisting of OR¹², NR¹²R¹³, C₁–C₈ alkyl,C₃–C₆ alkenyl, C₃–C₁₀ cycloalkyl(C₀–C₄ alkyl)-, C₆–C₁₀ aryl(C₀–C₄alkyl)-, and heterocyclic(C₀–C₄ alkyl)-,

wherein said aryl or heterocyclic groups are substituted with 0–3substituents independently selected from R¹⁴, with the proviso that whenL is a single bond, X cannot be NR¹²R¹³;

R¹² is selected from the group consisting of H, C₁–C₈ alkyl, C₃–C₆alkenyl, C₃–C₁₀ cycloalkyl(C₀–C₄ alkyl)-, monocyclic or bicyclicaryl(C₀–C₄ alkyl)-, and monocyclic or bicyclic 5–10 memberedheterocyclic(C₀–C₄ alkyl)-, and —CZ¹Z²Z³,

wherein said aryl or heterocyclic groups are substituted with 0–3substituents independently selected from R¹⁴;

Z¹ is selected from the group consisting of C₁–C₈ alkyl, C₂–C₆ alkenyl,C₂–C₆ alkynyl, C₁–C₆ hydroxyalkyl, C₁–C₄ alkoxy C₁–C₄ alkyl, aryl(C₀–C₄alkyl)-, and 4–10 membered heterocyclic (C₀–C₄ alkyl)-,

wherein said aryl or heterocyclic groups are substituted with 0–3substituents independently selected from R¹⁴;

Z² is selected from the group consisting of C₁–C₈ alkyl, C₂–C₆ alkenyl,C₂–C₆ alkynyl, C₁–C₆ hydroxyalkyl, C₁–C₄ alkoxy C₁–C₄ alkyl, C₁–C₆NR¹⁷R¹⁸, aryl(C₀–C₄ alkyl)-, and 4–10 membered heterocyclic (C₀–C₄alkyl)-,

wherein said aryl or heterocyclic groups are substituted with 0–3substituents independently selected from R¹⁴;

Z³ is selected from the group consisting of C₁–C₈ alkyl, R¹⁴(C₂–C₄alkyl)-, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ hydroxyalkyl, C₁–C₄ alkoxyC₁–C₄ alkyl, aryl(C₀–C₄ alkyl)-, 4–10 membered heterocyclic (C₀–C₄alkyl)-, R¹⁷O═C(C₀–C₄ alkyl)-, R¹⁷OO═C(C₀–C₄ alkyl)-, andR¹⁷R¹⁸NO═C(C₀–C₄ alkyl)-,

wherein said aryl or heterocyclic groups are substituted with 0–3substituents independently selected from R¹⁴;

alternatively, Z¹ and Z², when on the same carbon atom [as in(—CZ¹Z²—)], can be taken together with the carbon atoms to which theyare attached to form a 3–7 membered carbocyclic or 3–7 memberedheterocyclic non-aromatic ring system, said carbocyclic or heterocyclicring being optionally substituted with 0–2 substituents independentlyselected from R¹⁴.

R¹³ is selected from the group consisting of H, C₁–C₈ alkyl, C₃–C₆alkenyl, C₃–C₁₀ cycloalkyl(C₀–C₄ alkyl)-, C₁–C₆ alkylcarbonyl, C₁–C₆alkylsulfonyl, C₃–C₇ cycloalkyl(C₀–C₅ alkyl)carbonyl, C₁–C₆alkoxycarbonyl, C₃–C₇ cycloalkyl(C₀–C₅ alkoxy)carbonyl, aryl(C₀–C₄alkyl)-, aryl(C₁–C₅ alkoxy)carbonyl, arylsulfonyl, heterocyclic(C₀–C₄alkyl), heterocyclic(C₁–C₅ alkoxy)carbonyl, and heterocyclicsulfonyl,

wherein said aryl or heterocyclic groups are substituted with 0–2substituents independently selected from the group consisting of C₁–C₄alkyl, C₁–C₄ alkoxy, F, Cl, Br, CF₃, CN, and NO₂;

alternatively, R¹² and R¹³, when both are on the same nitrogen atom [asin (—NR¹²R¹³)] can be taken together with the nitrogen atom to whichthey are attached to form a heterocycle selected from 1-aziridinyl,1-azetidinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl,thiamorpholinyl, thiazolidinyl, and 1-piperazinyl,

said heterocycle being optionally substituted with 0–3 groupsindependently selected from oxo, C₁–C₆ alkyl, C₃–C₇ cycloalkyl(C₀–C₄alkyl)-, C₁–C₆ alkylcarbonyl, C₃–C₇ cycloalkyl(C₀–C₅ alkyl)carbonyl,C₁–C₆ alkoxycarbonyl, C₃–C₇ cycloalkyl(C₀–C₅ alkoxy)carbonyl, aryl(C₀–C₅alkyl), heterocyclic(C₀–C₅ alkyl), aryl(C₁–C₅ alkoxy)carbonyl,heterocyclic(C₁–C₅ alkoxy)carbonyl, C₁–C₆ alkylsulfonyl arylsulfonyl andheterocyclicsulfonyl,

wherein said aryl or heterocyclic groups are substituted with 0–2substituents independently selected from the group consisting of CH₃—,alkoxy, F, Cl, Br, CF₃, CN, and NO₂;

R¹⁴ is selected from the group consisting of H, C₁–C₁₀ alkyl, NO₂, CF₃,CN, F, Cl, Br, C₁–C₁₀ alkylcarbonyl, haloalkyl, haloalkoxy, OH,NR⁶R⁷(C₀–C₄ alkyl)-, R⁶ C(═O)O(C₀–C₄ alkyl)-, R⁶OC(═O)O(C₀–C₄ alkyl)-,R⁶O(C₀–C₄ alkyl), R⁶R⁷NC(═O)O(C₀–C₄ alkyl)-, R⁶R⁷NC(═O)(C₀–C₄ alkyl)-,R⁶O(CR¹⁰R¹¹)₂₋₆R⁶NC(═O)(C₀–C₄ alkyl)-, R⁶R⁷N(CR¹⁰R¹¹)₂₋₆R⁶NC(═O)(C₀–C₄alkyl)-, R⁶O₂C(CH₂)₁₋₄O(C₀–C₄ alkyl)-, R⁶OOC(C₁–C₄ alkoxy)-, R⁶OOC(C₀–C₄alkyl)-, R⁶C(═O)(C₀–C₄ alkyl)-, R⁶C(═O)NR⁷(C₀–C₄ alkyl)-,R⁶OC(═O)NR⁷(C₀–C₄ alkyl)-, R⁶OC(═NCN)NR⁷(C₀–C₄ alkyl)-,R⁶R⁷NC(═O)NR⁸(C₀–C₄ alkyl)-, R⁶OC(═NC)NR⁷(C₀–C₄ alkyl)-,R⁶(CR¹⁰R¹¹)₁₋₄NR⁷C═O—, R⁶O(CR¹⁰R¹¹))₁₋₄O═CR⁷N—,NR⁶R⁷(CR¹⁰R¹¹)₁₋₄C═OR⁷N—, R⁶O(CR¹⁰R¹¹)₂₋₄R⁷N—, R⁶O₂C(CR¹⁰R¹¹)₁₋₄R⁷N,R⁶R⁷N(CR¹⁰R¹¹)₂₋₄R⁷N—, R⁶R⁷NC(═NCN)NR⁷(C₀–C₄ alkyl)-,R⁶R⁷NC(═C(H)(NO₂))NR⁷(C₀–C₄ alkyl)-, R⁷R⁸NC(═NR⁷)NR⁷(C₀–C₄ alkyl)-,R⁶R⁷NSO₂NR⁸(C₀–C₄ alkyl)-, R⁶SO₂NR⁷(C₀–C₄ alkyl)-, R⁶R⁷N(C₁–C₄)CO—,R⁶R⁷N(C₂–C₆ alkyl)O—, R⁶CO(CR¹⁰R¹¹)₀₋₂R⁷N(O₂)S(C₀–C₄ alkyl),R⁶(O₂)SR⁷NC(═O) (C₀–C₄ alkyl)-, R⁶S(C₀–C₄ alkyl)-, R⁶S(═O)(C₀–C₄alkyl)-, R⁶SO₂(C₀–C₄ alkyl)-, SO₂NR⁶R⁷, SiMe₃, R⁶R⁷N(C₂–C₄ alkyl)-,R⁶R⁷N(C₂–C₄ alkoxy)-, HSO₃, HONH—, R⁶ONH—, R⁸R⁷NNR⁶—, HO(COR⁶)N—,HO(R⁶O₂C)N, C₂–C₆ alkenyl, C₃–C₁₀ cycloalkyl, C₃–C₁₀ cycloalkylmethyl,aryl(C₀–C₄alkyl)-, heteroaryl(C₀–C₄alkyl)-, aryl(C₀–C₄alkyl)O—, andheteroaryl(C₀–C₄alkyl)O—,

wherein said aryl groups are substituted with 0–2 substituentsindependently selected from a group consisting of C₁–C₄ alkyl, C₁–C₄alkoxy, F, Cl, Br, CF₃, and NO₂;

R¹⁵ is selected from the group consisting of H, halo, cyano, C₁–C₈alkyl, C₃–C₆ alkenyl, and C₃–C₁₀ cycloalkyl(C₀–C₄ alkyl)-, aryl(C₀–C₄alkyl)-, and heterocyclic(C₀–C₄ alkyl)-,

wherein said aryl or heterocyclic groups are substituted with 0–2substituents independently selected from R¹⁴;

R¹⁶ is selected from the group consisting of H, halo, cyano, C₁–C₈alkyl, C₃–C₆ alkenyl, C₃–C₁₀ cycloalkyl(C₀–C₄ alkyl)-, aryl(C₀–C₄alkyl)-, and heterocyclic(C₀C₄ alkyl)-,

wherein said aryl or heterocyclic groups are substituted with 0–2substituents independently selected from R¹⁴;

alternatively, when R¹⁵ and R¹⁶ are on adjacent carbon atoms [as in—HR¹⁵C—CHR¹⁶—], or when R¹⁵ and R¹⁶ are oriented on the same side of thedouble bond [as in the following structure (III)

R¹⁵ and R¹⁶ can be taken together with the carbon atoms to which theyare attached to form a 3–7 membered carbocyclic aromatic or nonaromaticring system, or a 3–7 membered heterocyclic aromatic or nonaromatic ringsystem, said carbocyclic or heterocyclic ring being optionallysubstituted with 0–2 substituents independently selected from the groupconsisting of C₁–C₄ alkyl, C₁–C₄ alkoxy, F, Cl, Br, CF₃, NO₂.

R¹⁷ is selected from the group consisting of H, C₁–C₈ alkyl, C₃–C₆alkenyl, C₃–C₁₀ cycloalkyl(C₀–C₄ alkyl)-, C₁–C₆ alkylcarbonyl, C₁–C₆alkylsulfonyl, C₃–C₇ cycloalkyl(C₀–C₅ alkyl)carbonyl, C₁–C₆alkoxycarbonyl, C₃–C₇ cycloalkyl(C₀–C₅ alkoxy)carbonyl,hydroxy(C₂–C₄)alkyl-, C₁–C₃ alkoxy(C₂–C₄)alkyl-, (C₀–C₄ alkyl) (C₀–C₄alkyl) amino(C₂–C₄)alkyl-, aryl(C₀–C₄ alkyl)-, aryl(C₁–C₅alkoxy)carbonyl, arylsulfonyl, heterocyclic(C₀–C₄ alkyl),heterocyclic(C₁–C₅ alkoxy)carbonyl, and heterocyclicsulfonyl,

wherein said aryl or heterocyclic groups are substituted with 0–2substituents independently selected from the group consisting of C₁–C₄alkyl, C₁–C₄ alkoxy, C₁–C₄ alkoxy C₁–C₄ alkyl, oxo, F, Cl, Br, CF₃, CN,and NO₂;

R¹⁸ is selected from the group consisting of H, C₁–C₈ alkyl, C₃–C₆alkenyl, C₃–C₁₀ cycloalkyl(C₀–C₄ alkyl)-, aryl(C₀–C₄ alkyl)-, andheterocyclic(C₀–C₄ alkyl),

wherein said aryl or heterocyclic groups are substituted with 0–2substituents independently selected from the group consisting of C₁–C₄alkyl, C₁–C₄ alkoxy, F, Cl, Br, CF₃, CN, and NO₂; and

alternatively, R¹⁷ and R¹⁸, when both are on the same nitrogen atom [asin (—NR¹²R¹³)] can be taken together with the nitrogen atom to whichthey are attached to form a heterocycle selected from 1-aziridinyl,1-azetidinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl,thiamorpholinyl, thiazolidinyl, and 1-piperazinyl,

said heterocycle being optionally substituted with 0–3 groups selectedfrom oxo, C₁–C₆ alkyl, C₃–C₇ cycloalkyl(C₀–C₄ alkyl)-, C₁–C₆alkylcarbonyl, (C₁–C₆ alkylcarbonyl)(C₀–C₄alkyl)amino-, C₃–C₇cycloalkyl(C₀–C₅ alkyl)carbonyl, C₁–C₆ alkoxycarbonyl, C₃–C₇cycloalkyl(C₀–C₅ alkoxy)carbonyl, aryl(C₀–C₅ alkyl), heterocyclic(C₀–C₅alkyl), aryl(C₁–C₅ alkoxy)carbonyl, heterocyclic(C₁–C₅ alkoxy)carbonyl,C₁–C₆ alkylsulfonyl arylsulfonyl and heterocyclicsulfonyl,

wherein said aryl or heterocyclic groups are substituted with 0–2substituents independently selected from the group consisting of CH₃—,alkoxy, F, Cl, Br, CF₃, CN, and NO₂.

Preferred are compounds of Formula I, including stereoisomeric formsthereof, tautomeric forms thereof, pharmaceutically acceptable saltforms thereof, or prodrug forms thereof,

wherein:

Z is either a 5, 6 or 7 membered monocyclic ring system substituted withR³ or R⁴ and optionally substituted with 0–4 substituents chosen from R¹or R², or a 9 or 10 membered bicyclic ring system optionally substitutedwith 0–5 substituents chosen from R¹, R², R³ or R⁴, said ring systemsoptionally contain up to 4 heteroatoms selected from N, O, and S, andwherein a CH₂ adjacent to any of the said N, O or S heteroatoms isoptionally substituted with oxo (═O);

R³ is a 5- or 6-membered heterocyclic ring system containing up to 4heteroatoms selected from N, O, and S, said heterocyclic ring systembeing optionally substituted with 0–1 R⁵, wherein when R⁵ is hydroxy theheterocycle may undergo tautomerization to an oxo species or may existas an equilibrium mixture of both tautomers;

J and K are taken together to be selected from: —NHC(═O)—, —NHCHR⁹—, and—C(═O)NH—;

X is selected from the group consisting of OR¹², NR¹²R¹³, C₃–C₁₀cycloalkyl(C₀–C₄ alkyl)-, C₆–C₁₀ aryl(C₀–C₄ alkyl)-, andheterocyclic(C₀–C₄ alkyl)-,

wherein said aryl or heterocyclic groups are substituted with 0–3substituents independently selected from R¹⁴, with the proviso that whenL is a single bond, X cannot be NR¹²R¹³;

R¹² is selected from the group consisting of ethyl, C₃–C₁₀cycloalkyl(C₀–C₄ alkyl)-, monocyclic or bicyclic aryl(C₀–C₄ alkyl)-, andmonocyclic or bicyclic 5–10 membered heterocyclic(C₀–C₄ alkyl)-, and—CZ¹Z²Z³,

wherein said aryl or heterocyclic groups are substituted with 0–3substituents independently selected from R¹⁴;

and all other constituents are as previously described.

All references cited herein are incorporated by reference in theirentirety.

In the description above and elsewhere in the specification, includingthe claims, each occurrence of a particular constituent is independentof each other occurrence of that same constituent.

Listed below are definitions of various terms used in the specificationand claims to describe the present invention.

The term “alkyl” refers to straight or branched chain alkyl.

The term “C_(integer)–C_(integer)” refers to a variable number of carbonatoms in a group depending on the integer values, as in C₀–C₄alkyl,which is meant to indicate a straight or branched alkyl group containing0–4 carbon atoms. A group with 0 (zero) carbon atoms indicates that thecarbon atom is absent i.e. there is a direct bond connecting adjacentterms. For example the term “C₀–C₄ alkylhydroxy” in the case “C₀” ismeant to indicate the group hydroxy.

The term “halogen” or “halo” refers to fluorine, chlorine, bromine oriodine.

The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbonshaving 6 to 12 carbon atoms in the ring portion, such as phenyl,naphthyl, biphenyl and diphenyl groups which may be optionallysubstituted.

The term “alkenyl” refers to straight or branched chain alkenyl groups.

The term “alkynyl” refers to straight or branched chain alkynyl.

The term “cycloalkyl” refers to an optionally substituted, saturatedcyclic hydrocarbon ring system.

The term “monocyclic” or “bicyclic” refers to either a “carbocyclic” ora “heterocyclic” ring system.

The term “carbocyclic” refer to an optionally substituted, fullysaturated or unsaturated, aromatic or nonaromatic cyclic group, which isa 3 to 7 membered monocyclic, or a 7 to 11 membered bicyclic, and allthe atoms in the ring are carbon atoms. Exemplary groups include phenyl,naphthyl, anthracenyl, cyclohexyl, cyclohexenyl and the like.

The terms “heterocycle” and “heterocyclic” refer to an optionallysubstituted, fully saturated or unsaturated, aromatic or nonaromaticcyclic group, which is a 3 to 7 membered monocyclic, or a 7 to 11membered bicyclic, which have at least one heteroatom and at least onecarbon atom in the ring. Each heterocyclic ring may contain 1, 2, 3, or4 heteroatoms selected from nitrogen, oxygen and sulfur, where thenitrogen and sulfur heteroatoms may also optionally be oxidized and thenitrogen heteroatoms may also optionally be quaternized. Theheterocyclic group may be attached via a nitrogen or carbon atom.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl,pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl,imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl,thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl,furanyl, tetrahydrofuranyl, thienyl, oxadiazolyl, piperidinyl,piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl,2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydrothiopyranyl,tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinylsulfoxide, tetrahydrothiopyranylsulfone, thiamorpholinyl sulfone,1,3-dioxolane, tetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl,thietanyl, thiiranyl, triazinyl, triazolyl, and the like.

Exemplary bicyclic heterocyclic groups include benzothiazolyl,benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl,quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl,benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl,coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl,furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,1-b]pyridinyl] orfuro[2,3-b]pyridinyl), pyrrolo[1,2-a]pyridinyl, 1,3-dioxindanyl,dihydroisoindolyl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl, benzisoxazolyl,benzodiazinyl, benzothiopyranyl, benzotriazolyl, benzpyrazolyl,dihydrobenzofuranyl, dihydrobenzothienyl, dihydrobenzothiopyranyl,dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl,indolyl, isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl,piperonyl, purinyl, pyridopyridyl, quinazolinyl, tetrahydroquinolinyl,thienofuryl, thienopyridyl, thienothienyl, and the like.

“IMPDH-associated disorders” refers to any disorder or disease state inwhich inhibition of the enzyme IMPDH (inosine monophosphatedehydrogenase, EC1.1.1.205, of which there are presently two knownisozymes referred to as IMPDH type 1 and IMPDH type 2) would modulatethe activity of cells (such as lymphocytes or other cells) and therebyameliorate or reduce the symptoms or modify the underlying cause(s) ofthat disorder or disease. There may or may not be present in thedisorder or disease an abnormality associated directly with the IMPDHenzyme. Examples of IMPDH-associated disorders include transplantrejection and autoimmune disorders, such as rheumatoid arthritis,multiple sclerosis, juvenile diabetes, asthma, and inflammatory boweldisease, as well as inflammatory disorders, cancer and tumor disorders,T-cell mediated hypersensitivity diseases, ischemic or reperfusioninjury, viral replication diseases, proliferative disorders and vasculardiseases.

As used herein the term “treating” includes prophylactic and therapeuticuses, and refers to the alleviation of symptoms of a particular disorderin a patient, the improvement of an ascertainable measurement associatedwith a particular disorder, or the prevention of a particular immuneresponse (such as transplant rejection). The term “patient” refers to amammal, preferably a human.

The compounds of this invention may contain one or more asymmetriccarbon atoms and thus may occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. All such isomers of the compounds disclosed herein areexpressly included within the scope of the present invention. Eachstereogenic carbon may be of the R or S configuration.

Combinations of substituents and variables thereof that result in stablecompounds are also contemplated within the present invention. The term“stable” as used herein refers to compounds which possess stabilitysufficient to allow manufacture and which maintain their integrity for asufficient period of time to be useful as a therapeutic or diagnosticagent.

As used herein, the compounds of this invention are defined to includepharmaceutically acceptable derivatives and prodrugs thereof. A“pharmaceutically acceptable derivative or prodrug” includes anypharmaceutically acceptable salt, ester, salt of an ester, or otherderivative of a compound of the present invention which, uponadministration to a subject, is capable of providing (directly orindirectly) a compound of the invention. Particularly favoredderivatives and prodrugs are those that increase the bioavailability ofthe compounds of the present invention when such compound isadministered to a subject (e.g., by allowing an orally administeredcompound to be more readily absorbed into the blood) or which enhancedelivery of the parent compound to a biological compartment (e.g., thebrain or lymphatic system) relative to the parent species. Preferredprodrugs include derivatives where a group that enhances aqueoussolubility or active transport through the gut membrane is appended to acompound of the present invention.

Pharmaceutically acceptable salts of the compounds disclosed hereininclude those derived from pharmaceutically acceptable inorganic andorganic acids and bases known to those skilled in the art. Examples ofsuitable acid salts include, but are not limited to, the following:acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate,bisulfate, butyrate, citrate, camphorate, camphorsulfonate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptanoate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate,palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, salicylate, succinate, sulfate, tartrate,thiocyanate, trifluoroacetic, tosylate and undecanoate. Other acids, forexample oxalic, while not in themselves pharmaceutically acceptable, maybe employed in the preparation of salts useful as intermediates inobtaining the compounds of the present invention and theirpharmaceutically acceptable acid additional salts.

Salts derived from appropriate bases include, but are not limited to,the following: alkali metal (e.g., sodium), alkaline earth metal (e.g.,magnesium), ammonium and N—(C₁₋₄ alkyl)₄ ⁺ salts. The present inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water-or oil-soluble ordispersible products may be obtained by such quaternization.

Methods of Preparation

The compounds of the present invention may be synthesized usingconventional techniques known in the art. Advantageously, thesecompounds are conveniently synthesized from readily available startingmaterials. Following are general synthetic schemes for manufacturingcompounds of the present invention. These schemes are illustrative andare not meant to limit the possible techniques one skilled in the artmay use to manufacture compounds disclosed herein. Different methodswill be evident to those skilled in the art. Additionally, the varioussteps in the synthesis may be performed in an alternate sequence ororder to give the desired compound(s). All documents cited herein areincorporated herein by reference in their entirety.

Compounds of the present invention can be made by many methods, whichwill be known to one skilled in the art of organic chemistry. Ingeneral, the time taken to complete a reaction procedure will be judgedby the person performing the procedure, preferably with the aid ofinformation obtained by monitoring the reaction by methods such as HPLCor TLC. A reaction does not have to go to completion to be useful tothis invention. The preparation of heterocycles useful to this inventionare described in the series of books: “Comprehensive HeterocyclicChemistry. The Structure, Reactions, Synthesis and Uses, of HeterocyclicCompounds” Katritzky, A. R., Rees, C. W. Ed's Pergamon Press New York,First edition 1984, and “Comprehensive Heterocyclic Chemistry II. AReview of the Literature 1982–1995. The Structure, Reactions, Synthesisand Uses, of Heterocyclic Compounds” Katritzky, A. R., Rees, C. W. andScriven, E., F. Ed's Pergamon Press New York, 1996. In general thecompounds of this invention can be prepared by the coupling of anappropriate amine or hydrazine with a carboxylic acid to provide thecompounds of interest, alternatively the compounds may be prepared bysimple alkylation of an amine or hydrazine, or reductive alkylation ofan amine or hydrazine. Examples of methods useful for the production ofcompounds of this invention are illustrated in schemes Ia–Vb.

Amines useful for the preparation of compounds useful to this inventionmay be commercially available or readily prepared by many methods knownto one skilled in the art of organic chemistry, and are described in“Comprehensive Organic Transformations. A Guide to Functional GroupPreparation.” pp- 385–439. Richard C. Larock 1989 VCH Publishers, Inc.Examples include but are not limited to, reduction of a nitro group,reduction of an azide and reduction of a nitrile.

A general method for the synthesis of the an amine useful in thisinvention can be perfomed by metal catalyzed cross coupling methodsknown in the literature. The simplest case is a Suzuki type crosscoupling (Miyaura, N., Yanagi, T. Suzuki, A., Synth. Comm. 11(7):513–519(1981); A. Suzuki et. al., J. Am. Chem. Soc. 111:513 (1989); and V. N.Kalinin, Russ. Chem. Rev. 60:173 (1991)) of an aryl boronic acid orester (Ia.1) (as shown below) with an appropriate bromoheterocycle inthe presence of a suitable catalyst such as tetrakis(triphenylphosphine)palladium. After the cross coupling has been performed the product maybe deprotected. The choice of protecting group and its method of removalwill be readily apparent to one skilled in the art of organic chemistry.Such considerations and methods are, for example, described by Greene,Theodora W. and Wuts, Peter G. M. in “Protective Groups in OrganicSynthesis.” 2nd Ed. (1991) Publisher: (John Wiley and Sons, Inc., NewYork, N.Y. For example, if the protecting group is acetyl the productmay be deprotected by treatment with aqueous potassium hydroxide at aconcentration of 0.5N to 5 N at room temperature to 100° C. for a periodbetween 0.5 h and 24 h.

For example aryl boronic acid (Ia.5) may react with the known5-bromothiazole (Ia.6) in the presence of tetrakis(triphenylphosphine)palladium (0), to provide (Ia.7) which may be deprotected by anappropriate method.

Copper has been recently been shown to be an effective catalyst forcross coupling of aryl boronic acids to N-unsubstituted heterocycles asdescribed by Chan. et al., Tetrahed. Lett. 39:2933–2936 (1998); and Lamet al., Tetrahed. Lett. 39:2941–2944 (1998). This results in compoundsin which the heterocycle is attached to the aryl ring through nitrogenrather than carbon. For example aryl boronic acid (Ia.5) may react withoxazolone (Ia.8) in the presence of copper (II) acetate in the presenceof an amine base such as pyridine to provide intermediate (Ia.9) whichmay be deprotected by an appropriate method.

In general aryl boronic acids and esters, Ib.3, where X is not Br or I,may be prepared as shown in Scheme Ib, from the correspondingarylbromide (Ib.1) by treatment with a palladium catalyst such as[1,1′-Bis(diphenylphosphino)-ferrocene] dichloropalladium (II) andbis(pinacolato)diboron, (Ib.2), as reported by Ishayama et al., J. Org.Chem., (1995) 7508–7510. Aryl boronic esters may be converted to thecorresponding boronic acid by several methods including treatment withaqueous HCl. In a variation of the synthesis, the nitrogen may be maskedas a nitro group and later reduced by several means including metalreductions, such as by treatment with tin chloride in HCl or byrefluxing the nitro compound with zinc in the presence of CaCl₂ in asolvent such as ethanol, or in certain cases the nitro group may bereduced by catalytic hydrogenation in the presence of catalysts such aspalladium on carbon. The conditions for the reduction of nitro groupsare detailed in several references including Hudlicky, M., “Reductionsin Organic Chemistry”, 2nd Ed., ACS Monograph 188, 1996, pp 91–101American Chemical Society, Washington, D.C. A second variation of thesynthesis allows the aryl bromide to remain through the entire synthesisand elaborated to the boronic acid at the end. This may eliminate theneed for a protecting group.

In certain cases it may be more expedient to construct the heterocyclicring by other methods. A general method for the synthesis of 5-memberedheterocycles includes the 1,3-dipolar cycloaddition reaction, which iswell known to one skilled in the art of organic chemistry and isdescribed by Padwa, Albert; Editor. in “1,3-Dipolar CycloadditionChemistry, Vol. 2” (1984) John Wiley and Sons, New York, N.Y.; andPadwa, Albert; Editor. in “1,3-Dipolar Cycloaddition Chemistry, Vol. 1”(1984) John Wiley and Sons, New York, N.Y. For example oxazoles may beprepared by 1,3 dipolar cycloaddtion of the corrosponding aldehyde(Ic.1) and (p-tolylsulfonyl)methyl isocyanate (TOSMIC) (Ic.2) as shownin scheme Ic. The aldehyde may be commercially available or preparedfrom the corresponding methyl group by oxidation with reagents such asCrO₃, MnO₂, and ammonium cerium (IV) nitrate by methods well known toone skilled in the art of organic chemistry and is described inHudlicky, M., “Oxidations in Organic Chemistry”, ACS Monograph 186(1990), American Chemical Society, Washington, D.C. The nitro group inintermediate (Ic.3), is reduced to an amine (Ic.4), as discussed above.

An alternative method of producing amines useful to this invention is bynucleophilic attack an an electron deficient ring system as outlined inscheme Id. Halonitrobenzenes (Id. 1), are either commercially availableor readily prepared by methods known to one skilled in the art oforganic synthesis. Displacement with a variety of nucleophiles producecompounds of structure (Id.2). In one example heating (Id.3) with anucleophilic heterocycle such as triazole with or without the additionof a base provides the intermediate nitro compound which may be reducedas previously describe to provide amines (Id.4). Alternatively simpleorganic nucleophiles such as cyanide can be reacted withhalonitrobenzene (Id.5) to provide an intermediate nitrocompound whichcan be reduced by many methods to amine (Id.6).

Scheme IIa, IIb, IIc, depicts the coupling of the amines prepared inScheme Ia and Ib to various acids. The acids useful in this inventionare either commercially available such as ethyl oxalyl chloride, ethylmalonyl chloride, chloroacetyl chloride, benzoyl formate or indol-2-ylcarboxylic acid, or readily prepared by one skilled in the art oforganic chemistry. Carboxylic acids may also be prepared by thehydrolysis of carbocylic acid esters. The coupling is carried out usingany of the many methods for the formation of amide bonds known to oneskilled in the art of organic synthesis. These methods include but arenot limited to conversion of the acid to the corresponding acidchloride, or use of standard coupling procedures such as the azidemethod, mixed carbonic acid anhydride (isobutyl chloroformate) method,carbodiimide (dicyclohexylcarbodiimide, diisopropylcarbodiimide, orwater-soluble carbodiimides) method, active ester (p-nitrophenyl ester,N-hydroxysuccinic imido ester) method, carbonyldiimidazole method,phosphorus reagents such as BOP-Cl. Some of these methods (especiallythe carbodiimide) can be enhanced by the addition of1-hydroxybenzotriazole.

Thus amine (IIa.1) may be coupled with acid chloride (IIa.2) in thepresence of an amine base such as triethylamine to produce amide(IIa.3). Ester (IIa.3) is also a useful intermediate. The ester may behydrolized by treatment with aqueous base such as sodium hydroxide toproduce acid (IIa.4). This acid can be coupled with a second amine toproduce the bisamide (IIa.5). The amines useful to this invention arecommercially available, or are readily prepared from commercial startingmaterials by one skilled in the art of organic chemistry.

In the case of carboxylic acid derivatives which contain an □-halo atom,such as chlorine or bromine, the product may be used as an intermediate.Such reagents readily react with amines in the presence of a suitablebase to provide □-aminoacids useful to this invention. For example inScheme IIb, amine (IIb.1) is coupled with chloroacetyl chloride,(IIb.2), to produce intermediate (IIb.3) which can be heated in thepresence of an amine with or without the addition of a base to providecompound (IIb.4).

Scheme IIc depicts the coupling of the amine to a heterocyclic acid.This can be accomplished with many of the coupling agents describedpreviously. The heterocyclic carboxylic acids are either commerciallyavailable or readily prepared by methods known to one skilled in the artof organic chemistry. For example many heterocycles undergoregioselective lithiation; this intermediate may be treated with CO₂ gasor solid to provide the required carboxylic acids. For example amine(IIc.1), may be coupled with acid (IIc.2) to provide the desired product(IIc.3).

Carboxylic acid derivative useful for this invention are eithercommercially available or readily prepared by one skilled in the art oforganic chemistry. The preparation of carboxylic acids and relatedfunctional groups such as carboxylic acid esters are described in“Comprehensive Organic Transformations. A Guide to Functional GroupPreparation.” Richard C. Larock 1989 VCH Publishers, Inc. Carboxylicacids can be prepared by a number of methods not limited to ozonolysisof an alkene, ozonolysis of a furan ring, oxidation of a alkyl groupwhen attached to an aryl ring, oxidation of a primary alcohol,hydrolysis of a nitrile, carbonylation procedures, and homologation ordegradation of an existing carboxylic acid.

Scheme IIIa illustrates the preparation of a carboxylic acid derivativeuseful as an intermediate for this invention. The preparation of methyl4-formyl-3-methoxybenzoate (IIIa.1) has been reported by Griera, R. etal. in European Journal of Medicinal Chemistry (1997) pp 547–570.Reaction of the aldehyde with TOSMIC as described in scheme Ic, followedby acidification precipitates the desired acid.

Hydrazines useful as intermediates in this invention are eithercommercially available or may be prepared by many methods known to oneskilled in the art of organic synthesis including reduction of diazoniumsalts as illustrated in scheme IVa.

Aldehydes and ketones useful as intermediates in this invention areeither commercially available or may be readily prepared by by manymethods known to one skilled in the art of organic synthesis and areillustrated in “Comprehensive Organic Transformations. A Guide toFunctional Group Preparation.” Richard C. Larock 1989 VCH Publishers,Inc. Examples of methods for production of aldehydes include but are notlimited to oxidation of a primary alcohol, reduction of carboxylic acidester, or ozonolysis of an alkene. Examples of methods for production ofketones include but are not limited to oxidation of secondary alcohols,and oxidative cleavage of alkenes.

Compounds useful to this invention may also be prepared by reductiveamination using either amines or hydrazines and an aldehyde. A usefulmethod of performing reductive aminations has been described byAbdel-Magid, A. F., et al in Journal of Organic Chemistry (1996) pp3849–3862. This method involves dissolving the aldehyde or ketone and anamine or hydrazine in a suitable solvent such as 1,2-dichloroethane inthe presence of sodium triacetoxyborohydride. Reductive amination isillustrated in scheme Va.

Scheme Vb illustrates alkylation as a means of forming the nitrogencarbon bond. Amine (Iic.1) may be readily alkylated by □-haloamides, byheating in a solvent such as N,N-dimethylformamide with or without theaddition of a base such as potassium carbonate to provide compounds oftype (Vb.1). Alkylation of amine (Iic.1) with an allylic halide in asolvent such as N,N-dimethylformamide in the presence or absence of abase provides the alkylated compounds (Vb.2) The reactions illustratedin scheme Vb, generally require purification by a method such as flashcolumn chromatogaphy or prepraratory high performance liquidchormatography (HPLC) to provide the desired product. Such methods wouldbe known to one skilled in the art of organic chemistry.

Utility

The compounds of the present invention inhibit IMPDH enzyme, and arethus useful in the treatment, including prevention and therapy, ofdisorders which are mediated or effected by cells which are sensitive toIMPDH inhibition, as described previously. The present invention thusprovides methods for the treatment of IMPDH-associated disorders,comprising the step of administering to a subject in need thereof atleast one compound of the formula I, in an amount effective therefor.Other therapeutic agents, such as those described below, may be employedwith the inventive compounds in the present methods. In the methods ofthe present invention, such other therapeutic agent(s) may beadministered prior to, simultaneously with or following theadministration of the compound(s) of the present invention.

Use of the compounds of the present invention in treating exemplifiedby, but is not limited to, treating a range of disorders such as:treatment of transplant rejection (e.g., kidney, liver, heart, lung,pancreas (e.g., islet cells), bone marrow, cornea, small bowel, skinallografts, skin homografts (such as employed in burn treatment), heartvalve xenografts, serum sickness, and graft vs. host disease, in thetreatment of autoimmune diseases, such as rheumatoid arthritis,psoriatic arthritis, multiple sclerosis, juvenile diabetes, asthma,inflammatory bowel disease (such as Crohn's disease and ulcerativecolitus), pyoderma gangrenum, lupus (systemic lupus erythematosis),myasthenia gravis, psoriasis, dermatitis, dermatomyositis; eczema,seborrhoea, pulmonary inflammation, eye uveitis, hepatitis, Grave'sdisease, Hashimoto's thyroiditis, autoimmune thyroiditis, Behcet's orSjorgen's syndrome (dry eyes/mouth), pernicious or immunohaemolyticanaemia, Addison's disease (autoimmune disease of the adrenal glands),idiopathic adrenal insufficiency, autoimmune polyglandular disease (alsoknown as autoimmune polyglandular syndrome), glomerulonephritis,scleroderma, morphea, lichen planus, viteligo (depigmentation of theskin), alopecia greata, autoimmune alopecia, autoimmune hypopituatarism,Guillain-Barre syndrome, and alveolitis; in the treatment of T-cellmediated hypersensitivity diseases, including contact hypersensitivity,delayed-type hypersensitivity, contact dermatitis (including that due topoison ivy), uticaria, skin allergies, respiratory allergies (hayfever,allergic rhinitis) and gluten-sensitive enteropathy (Celiac disease); inthe treatment of inflammatory diseases such as osteoarthritis, acutepancreatitis, chronic pancreatitis, asthma, acute respiratory distresssyndrome, Sezary's syndrome and vascular diseases which have aninflammatory and or a proliferatory component such as restenosis,stenosis and artherosclerosis; in the treatment of cancer and tumordisorders, such as solid tumors, lymphomas and leukemia; in thetreatment of fungal infections such as mycosis fungoides; in protectionfrom ischemic or reperfusion injury such as ischemic or reperfusioninjury that may have been incurred during organ transplantation,myocardial infarction, stroke or other causes; in the treatment of DNAor RNA viral replication diseases, such herpes simplex type 1 (HSV-1),herpes simplex type 2 (HSV-2), hepatitis (including hepatitis B andhepatitis C) cytomegalovirus, Epstein-Barr, and human immunodeficiencyvirus (HIV).

Additionally, IMPDH is also known to be present in bacteria and thus mayregulate bacterial growth. As such, the IMPDH-inhibitor compounds of thepresent invention may be useful in treatment or prevention of bacterialinfection, alone or in combination with other antibiotic agents.

In a particular embodiment, the compounds of the present invention areuseful for the treatment of the aforementioned exemplary disordersirrespective of their etiology, for example, for the treatment oftransplant rejection, rheumatoid arthritis, inflammatory bowel disease,and viral infections.

The present invention also provides pharmaceutical compositionscomprising at least one of the compounds of formula I, or a saltthereof, capable of treating an IMPDH-associated disorder in an amounteffective therefor, alone or in combination with at least one additionaltherapeutic agent, and any pharmaceutically acceptable carrier, adjuvantor vehicle. “Additional therapeutic agents” encompasses, but is notlimited to, an agent or agents selected from the group consisting of animmunosuppressant, an anti-cancer agent, an anti-viral agent, ananti-inflammatory agent, an anti-fungal agent, an antibiotic, or ananti-vascular hyperproliferation compound.

The term “pharmaceutically acceptable carrier, adjuvant or vehicle”refers to a carrier, adjuvant or vehicle that may be administered to asubject, together with a compound of the present invention, and whichdoes not destroy the pharmacological activity thereof. Pharmaceuticallyacceptable carriers, adjuvants and vehicles that may be used in thepharmaceutical compositions of the present invention include, but arenot limited to, the following: ion exchangers, alumina, aluminumstearate, lecithin, self-emulsifying drug delivery systems (“SEDDS”)such as d(-tocopherol polyethyleneglycol 1000 succinate), surfactantsused in pharmaceutical dosage forms such as Tweens or other similarpolymeric delivery matrices, serum proteins such as human serum albumin,buffer substances such as phosphates, glycine, sorbic acid, potassiumsorbate, partial glyceride mixtures of saturated vegetable fatty acids,water, salts or electrolytes such as protamine sulfate, disodiumhydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zincsalts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat. Cyclodextrins such as α-, β- and γ-cyclodextrin, or chemicallymodified derivatives such as hydroxyalkylcyclodextrins, including 2- and3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives mayalso be used to enhance delivery of the compounds of the presentinvention.

The compositions of the present invention may contain other therapeuticagents as described below, and may be formulated, for example, byemploying conventional solid or liquid vehicles or diluents, as well aspharmaceutical additives of a type appropriate to the mode of desiredadministration (for example, excipients, binders, preservatives,stabilizers, flavors, etc.) according to techniques such as those wellknown in the art of pharmaceutical formulation.

The compounds of the formula I may be administered by any suitablemeans, for example, orally, such as in the form of tablets, capsules,granules or powders; sublingually; buccally; parenterally, such as bysubcutaneous, intravenous, intramuscular, or intrasternal injection orinfusion techniques (e.g., as sterile injectable aqueous or non-aqueoussolutions or suspensions); nasally such as by inhalation spray;topically, such as in the form of a cream or ointment; or rectally suchas in the form of suppositories; in dosage unit formulations containingnon-toxic, pharmaceutically acceptable vehicles or diluents. The presentcompounds may, for example, be administered in a form suitable forimmediate release or extended release. Immediate release or extendedrelease may be achieved by the use of suitable pharmaceuticalcompositions comprising the present compounds, or, particularly in thecase of extended release, by the use of devices such as subcutaneousimplants or osmotic pumps. The present compounds may also beadministered liposomally.

Exemplary compositions for oral administration include suspensions whichmay contain, for example, microcrystalline cellulose for imparting bulk,alginic acid or sodium alginate as a suspending agent, methylcelluloseas a viscosity enhancer, and sweeteners or flavoring agents such asthose known in the art; and immediate release tablets which may contain,for example, microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and/or lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants such as those known inthe art. The present compounds may also be delivered through the oralcavity by sublingual and/or buccal administration. Molded tablets,compressed tablets or freeze-dried tablets are exemplary forms which maybe used. Exemplary compositions include those formulating the presentcompound(s) with fast dissolving diluents such as mannitol, lactose,sucrose and/or cyclodextrins. Also included in such formulations may behigh molecular weight excipients such as celluloses (avicel) orpolyethylene glycols (PEG). Such formulations may also include anexcipient to aid mucosal adhesion such as hydroxy propyl cellulose(HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methylcellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agentsto control release such as polyacrylic copolymer (e.g., Carbopol 934).Lubricants, glidants, flavors, coloring agents and stabilizers may alsobe added for ease of fabrication and use.

Exemplary compositions for nasal aerosol or inhalation administrationinclude solutions in saline which may contain, for example, benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, and/or other solubilizing or dispersing agents such asthose known in the art.

Exemplary compositions for parenteral administration include injectablesolutions or suspensions which may contain, for example, suitablenon-toxic, parenterally acceptable diluents or solvents, such asmannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodiumchloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid. The term “parenteral” as used hereinincludes subcutaneous, intracutaneous, intravenous, intramuscular,intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal,intralesional and intracranial injection or infusion techniques.

Exemplary compositions for rectal administration include suppositorieswhich may contain, for example, a suitable non-irritating excipient,such as cocoa butter, synthetic glyceride esters or polyethyleneglycols, which are solid at ordinary temperatures, but liquify and/ordissolve in the rectal cavity to release the drug.

Exemplary compositions for topical administration include a topicalcarrier such as Plastibase (mineral oil gelled with polyethylene).

The effective amount of a compound of the present invention may bedetermined by one of ordinary skill in the art, and includes exemplarydosage amounts for an adult human of from about 0.1 to 500 mg/kg of bodyweight of active compound per day, which may be administered in a singledose or in the form of individual divided doses, such as from 1 to 5times per day. It will be understood that the specific dose level andfrequency of dosage for any particular subject may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the species, age, body weight, general health, sex and diet ofthe subject, the mode and time of administration, rate of excretion,drug combination, and severity of the particular condition. Preferredsubjects for treatment include animals, most preferably mammalianspecies such as humans, and domestic animals such as dogs, cats and thelike, subject to IMPDH-associated disorders.

The compounds of the present invention may be employed alone or incombination with each other and/or other suitable therapeutic agentsuseful in the treatment of IMPDH-associated disorders, such as IMPDHinhibitors other than those of the present invention,immunosuppressants, anti-cancer agents, anti-viral agents,anti-inflammatory agents, anti-fungal agents, antibiotics, oranti-vascular hyperproliferation agents.

Exemplary such other therapeutic agents include the following:cyclosporins (e.g., cyclosporin A), CTLA4-Ig, antibodies such asanti-ICAM-3, anti-IL-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2,anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, monoclonal antibodyOKT3, agents blocking the interaction between CD40 and CD154 (a.k.a.“gp39”), such as antibodies specific for CD40 and/or CD154, fusionproteins constructed from CD40 and/or CD154/gp39 (e.g., CD40Ig andCD8gp39), inhibitors, such as nuclear translocation inhibitors, ofNF-kappa B function, such as deoxyspergualin (DSG), non-steroidalantiinflammatory drugs (NSAIDs) such as ibuprofen, celecoxib androfecoxib, steroids such as prednisone or dexamethasone, gold compounds,antiviral agents such as abacavir, antiproliferative agents such asmethotrexate, leflunomide, FK506 (tacrolimus, Prograf), cytotoxic drugssuch as azathiprine and cyclophosphamide, TNF-α inhibitors such astenidap, anti-TNF antibodies or soluble TNF receptor, and rapamycin(sirolimus or Rapamune) or derivatives thereof.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention, may be used, for example, inthose amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art.

The compounds disclosed herein are capable of targeting and inhibitingIMPDH enzyme. Inhibition can be measured by various methods, including,for example, IMP dehydrogenase HPLC assays (measuring enzymaticproduction of XMP and NADH from IMP and NAD) and IMP dehydrogenasespectrophotometric assays (measuring enzymatic production of NADH fromNAD). See, e.g., Montero et al., Clinica Chimica Acta 238:169–178(1995). Additional assays known in the art can be used in ascertainingthe degree of activity of a compound (“test compound”) as an IMPDHinhibitor. The inventors used the following assay to determine thedegree of activity of the compounds disclosed herein as IMPDHinhibitors:

Activity of IMPDH I and IMPDH II was measured following an adaptation ofthe method described in WO 97/40028. The reaction mixture was preparedcontaining 0.1M Tris pH 8.0, 0.1 M KCl, 3 mM EDTA, 2 mM DTT, 0.4 mM IMPand 40 nM enzyme (IMPDH I or IMPDH II). The reaction was started by theaddition of NAD to a final concentration of 0.4 mM. The enzymaticreaction was followed by measuring the increase in absorbance at 340 nMthat results from the formation of NADH. For the analysis of potentialinhibitors of the enzyme, compounds were dissolved in DMSO to a finalconcentration of 10 mM and added to the assay mixture such that thefinal concentration of DMSO was 2.5%. The assay was carried out in a96-well plate format, with a final reaction volume of 200 □l.

The compounds disclosed herein are capable of inhibiting the enzymeIMPDH at a measurable level, under the above-described assay or an assaywhich can determine an effect of inhibition of the enzyme IMPDH.

The following examples illustrate preferred embodiments of the presentinvention and do not limit the scope of the present invention, which isdefined in the claims. Abbreviations employed in the Examples aredefined below. Compounds of the Examples are identified by the exampleand step in which they are prepared (e.g., “1A” denotes the titlecompound of Example 1A), or by the example only where the compound isthe title compound of the example (for example, “2” denotes the titlecompound of Example 2).

Abbreviations Ac Acetyl AcOH Acetic acid aq. Aqueous CDICarbonyldiimidazole Bn Benzyl Boc tert-butoxycarbonyl DMAPDimethylaminopyridine DMF dimethylformamide DMSO Dimethylsulfoxide EDC1-(3-Dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride EtOAc Ethylacetate Et Ethyl EtOH Ethanol h Hours i iso HPLC High pressure liquidchromatography HOAc Acetic acid THF Tetrahydrofuran Lawesson's Reagent[2,4-bis(4-methoxyphenyl)-1,3- dithia-2,4-diphosphetane-2-4- disufide LCliquid chromatography Me Methyl MeOH Methanol min. Minutes M⁺ (M + H)⁺M⁺¹ (M + H)⁺ MS Mass spectrometry n normal Pd/C Palladium on carbon PhPhenyl Pr Propyl Ret Time Retention time rt or RT Room temperature sat.Saturated TFA Trifluoroacetic acid THF Tetrahydrofuran TOSMICTosylmethyl isocyanide YMC YMC Inc, Wilmington, NC 28403

The following LC/MS conditions were utilized:

-   LC/MS condition A, denoted as “ret. time^(A)”: Column: YMC S5 ODS    Ballistic column, 4.6×50 mm; 0% B–100% B, linear gradient over 4 min    at 4.0 ml/min; 1 min isocratic at 100% B; Solvent A: 10% MeOH—90%    H₂O-0.1% TFA; Solvent B: 90% MeOH—10% H₂O-0.1% TFA.-   LC/MS condition B, denoted as “ret. time^(B)”: Column: Shimadzu    4.6×50 mm Ballistic, 0% B–100% B, linear gradient over 4 min at 4.0    ml/min; 1 min isocratic at 100% B. Solvent A=10% MeOH, 90% H₂O, 0.1%    TFA. Solvent B=90% MeOH, 10% H₂O, 0.1% TFA.

EXAMPLE 1N-(4-Fluorophenyl)-N-2-[3-methoxy-4-(5-oxazolyl)phenyl]glycinamide

1A. 4-Nitro-2-methoxy-(α,α-bisacetoxy)toluene

To a 5 L three necked round bottom flask equipped with a mechanicalstirrer was added 4-nitro-2-methoxytoluene (150.0 g, 0.8973 mol), HOAc(900 mL) and Ac₂O (900 mL). The mixture was stirred and cooled to 8° C.with an acetone/ice bath. Concentrated H₂SO₄ (136 mL) was carefullyadded while keeping the pot temperature <19° C. After cooling to 0° C.,CrO₃ (252.6 g, 2.526 mol, 2.815 equiv.) was added portion-wise over 1hour while maintaining the reaction temperature between 0–10° C. Afterthe addition, the mixture was stirred at 0° C. for 30 minutes at whichtime the reaction was complete. The reaction mixture was then carefullypoured into ice (1.5 kg) with stirring to give a slurry. The remainingblack gummy residue was rinsed with HOAc (3×100 mL), and the washes wereadded to the slurry. After stirring for 10 minutes, the slurry wasfiltered. The cake was washed with water (3×400 mL) and suction driedfor 17 hours to give 1A (129.0 g, 51%). ¹H NMR (CDCl₃) d 8.02 (s, 1H),7.89 (d, J=8.4 Hz, 1H), 7.77 (s, 1H), (d, 8.4 Hz, 1H), 3.98 (s, 3H),2.16(s,6H).

1B. 4-Nitro-2-methoxybenzaldehyde

To a 2 L rounded bottom flask equipped with a condenser and a mechanicalstirrer was placed 1A (250.7 g, 0.8851 mol), dioxane (300 mL) andconcentrated HCl (60 mL). The reaction mixture was heated to reflux andstirred under N₂ for 20 hours. Water (250 mL) was added dropwise whilemaintaining the reaction mixture at reflux. After cooling to 0° C. withan ice/water bath, the resulting slurry was stirred for 30 minutes andthen filtered. The cake was washed with water (4×200 mL) and suctiondried for 17 hours to give 1B (146.3 g, 91%) as yellow solid. ¹H NMR(CDCl₃) d 10.54 (s, 1H), 8.00 (d, J=8.3 Hz, 1H), 7.91 (s, 1H), 7.89 (d,J=8.3 Hz, 1H), 4.08(s, 3H).

1C. 5-(4-Nitro-2-methoxyphenyl)oxazole

To a 5 L three necked round bottom flask equipped with a condenser and amechanical stirrer was placed 1B (146.3 g, 0.8076 mol), TOSMIC (157.7 g,0.8077 mol), K₂CO₃ (116.6 g, 0.8075 mol) and MeOH (2.5 L). The mixturewas heated to reflux under N₂ and stirred for 3 hours. Water (1.25 L)was added drop-wise while maintaining the pot temperature between 59–69°C. The resulting slurry was cooled to room temperature, and then to 5°C. with an ice-water bath. After stirring for 30 minutes at 5° C., theslurry was filtered. The resulting cake was washed with water (3×400 mL)and dried in a vacuum oven at 45° C. for 20 hours to give 1C (148.5 g,84%) as a yellow-reddish solid. ¹H NMR (CDCl₃) d 8.02 (s, 1H), 7.97 (d,J=2 Hz, 1H), 7.95 (d, J=2 Hz, 1H), 7.86 (s, 1H), 7.78 (s, 1H), 4.11 (s,3H).

1D. 5-(4-Amino-2-methoxyphenyl)oxazole

In a 2 L hydrogenation flask was placed 1C (130.0 g, 0.6131 mol), Pd/C(10%, 26.2 g) and absolute EtOH (1280 mL). The mixture was hydrogenatedat 35–45 psi H₂ until the reaction was complete. The mixture wasfiltered over a pad of celite (20 g) and the cake was washed with EtOH(3×100 mL). The filtrate was concentrated to a volume of 350 mL. Heptane(500 mL) was added to the resulting slurry. After stirring for 2 hoursat room temperature, the slurry was filtered. The cake was washed withheptane (3×100 mL) and air-dried to give 80.0 g of 1D. Another 30.2 g ofproduct was recovered from the mother liquor affording a total yield of95%. ¹H NMR (CDCl₃) d 7.88 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.41 (s,1H), 6.41 (dd, J=8.4, 2.1 Hz, 1H), 3.34 (d, J=2.1 Hz, 1H), 3.98 (bs,2H), 3.94 (s, 3H).

1. N-(4-Fluorophenyl)-N-2-[3-methoxy-4-(5-oxazolyl)phenyl]glycinamide

A solution of 1D, (101 mg, 0.53 mmol) and 2-chloro-4′-fluoroacetanilide(50 mg, 0.27 mmol) in DMF (0.15 mL) was heated at 100° C. for 15 h.After the reaction had cooled, the solvent was removed under reducedpressure, and the residue was subjected to preparative HPLC to give 1 asa tan solid. LC/MS: ret. time^(A)=3.527 min., MS (M+H)⁺=342.

EXAMPLE 2 N-[3-Methoxy-4-(5-oxazolyl)phenyl]-N-2-phenylglycinamide

2A. Preparation of 2-Chloro-N-[3-Methoxy-4-(5-oxazolyl)phenyl]-acetamide

To a solution of 1D (500 mg, 2.63 mmol) and triethylamine (370 μL, 2.89mmol) in dichloromethane (13.0 mL), was added chloroacetyl chloride(0.23 mL, 2.89 mmol) at 0° C. The reaction mixture was stirred at 0° C.for 10 min. and then at RT for 4 h. The mixture was diluted withdichloromathane, washed with water, brine, and dried over Na₂SO₄. Themixture was filtered through celite and concentrated in vacuo to give 2Aas a yellow solid. LC/MS: ret. time^(A)=3.123 min., MS (M+H)⁺=267.

2. Preparation ofN-[3-Methoxy-4-(5-oxazolyl)phenyl]-N-2-phenylglycinamide

A solution of 2A (30.0 mg, 0.11 mmol) and aniline (30 μL, 0.33 mmol) inDMF (0.1 mL) was heated at 100° C. for 2.5 h. After the reaction hadcooled, the solvent was removed under reduced pressure, and the residuewas subjected to preparative HPLC to give 2 as a yellow solid. LC/MS:ret. time^(A)=3.576 min., MS (M+H)⁺=324.

EXAMPLE 3N-[3-Methoxy-4-(5-oxazolyl)phenyl]-N-2-(3-methylphenyl)glycinamide

Compound 3 was prepared by a route analogous to that used for thepreparation of 2, replacing aniline with m-toluidine. LC/MS: ret.time^(A)=3.759 min., MS (M+H)⁺=338.

EXAMPLE 4 [[3-Methoxy-4-(5-oxazolyl)phenyl]amino]oxoacetic acid ethylester

To a solution of 1D (1.0 g, 5.26 mmol) and triethylamine (806 μL, 5.78mmol) in dichloromethane (26.3 mL), was added ethyl oxalyl chloride(0.646 μL, 5.78 mmol) at 0° C. The reaction mixture was stirred at 0° C.for 10 min. and then at RT for 15 h. The mixture was diluted withdichloromethane, washed with water, brine, and dried over Na₂SO₄.Following evaporative removal of the solvent, the residue waschromtographed on silica gel, eluting with 80:1 CH₂Cl₂:MeOH to give 4 asa yellow solid. LC/MS: ret. time^(A)=3.283 min., MS (M+H)⁺=291.

EXAMPLE 5 N-[3-Methoxy-4-(5-oxazolyl)phenyl]-N′-phenylethanediamide

5A. Preparation of [[3-Methoxy-4-(5-oxazolyl)phenyl]amino]oxoacetic acid

To a solution of 4 (1.45 g, 4.98 mmol) in EtOH (75.0 mL) was added 1NNaOH (12.4 mL, 12.45 mmol) at RT. After stirring for 15 h, the reactionmixture was neutralized with 1N HCl (12.4 mL, 12.45 mmol) and thenconcentrated to give 5A and NaCl. LC/MS: ret. time^(A)=2.661 min., MS(M+H)⁺=263.

5B. Preparation ofN-[3-Methoxy-4-(5-oxazolyl)phenyl]-N′-phenylethanediamide

A mixture of the crude product of 5A (47 mg, 0.114 mmol), aniline (10.6mg, 0.114 mmol), BOP (72.5 mg, 0.172 mmol), and NMM (58 mg, 0.57 mmol)in DMF (0.95 mL) was stirred at RT for 15 h. The mixture was dilutedwith ethyl acetate, washed with water, brine, and dried over Na₂SO₄.Following evaporative removal of the solvent, the residue was trituratedwith MeOH to give 5 as a yellow solid LC/MS: ret. time^(A)=3.960 min.,MS (M+H)⁺=338.

EXAMPLES 6 THROUGH 54

Compounds 6–54 were prepared from the product of 5A by a route analogousto that used for the preparation of 5, replacing aniline with therequired HN₂—G¹. The compounds of these examples have the structuresshown in Table 1:

TABLE 1

HPLC Ret MS Ex. No —G¹ Compound name Time^(A) (min) (M + H)⁺ 6

N-[3-Methoxy-4-(5-oxazolyl)phenyl]N′-(2-methylphenyl)ethanediamide 4.076352 7

N-[3-Methoxy-4-(5-oxazolyl)phenyl]N′-(3-methylphenyl)ethanediamide 4.162352 8

N-[3-Methoxy-4-(5-oxazolyl)phenyl]N′-(4-methylphenyl)ethanediamide 4.181352 9

(S)-[[3-[[[[3-Methoxy-4-(5-oxazolyl)phenyl]amino]oxoacetyl]amino]phenyl]methyl]carbamicacidtetrahydro-3-furanyl ester 3.722 481 10

N-[3-Methoxy-4-(5-oxazolyl)phenyl]N′-(3-methoxyphenyl)ethanediamide4.141 368 11

N-[3-Methoxy-4-(5-oxazolyl)phenyl]-N′-(phenylmethyl)ethanediamide 3.948352 12

N-(4-Cyanophenyl)-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide 3.843363 13

N-(1,1-Dimethylethyl)-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide4.07 318 14

N-[1,1-Bis(hydroxymethyl)propyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide3.34 364 15

N-(2-Hydroxy-1,1-dimethylethyl)-N′-[3-methoxy-4-oxazolyl)phenyl]ethanediamide3.51 334 16

N-[[[3-Methoxy-4-(5-oxazolyl)phenyl]amino]oxoacetyl]-2-methylalanine1,1-dimethylethyl ester 4.52 404 17

N-(2-Hydroxy-1,1-dimethylpentyl)-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide4.35 376 18

N-[2-[(2-Hydroxy-1,1-dimethylethyl)amino]-1,1-dimethylethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide2.88 405 19

N-[2-(Dimethylamino)-1,1-dimethylethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide2.75 361 20

N-(1,1-Diethyl-2-propynyl)-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide4.45 356 21

N-[3-Methoxy-4-(5-oxazolyl)phenyl]-N′-(1,1,3,3-tetramethylbutyl)ethanediamide4.25 374 22

N-(1,1-Dimethylpropyl)-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide4.47 332 23

N-[1-(Hydroxymethyl)cyclopentyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide3.94 360 24

N-[2-(4-Fluorophenyl)-1,1-dimethylethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide4.82 412 25

N-[[[3-Methoxy-4-(5- oxazolyl)phenyl]amino]oxoacetyl]-α-methyltyrosinemethyl ester 3.98 454 26

N-[[[3-Methoxy-4-(5-oxazolyl)phenyl]amino]oxoacetyl]-a-methyltryptophanmethylester 4.37 477 27

N-[1,1-Bis(hydroxymethyl)ethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]-N-methylethanediamide3.02 350 28

N-(1,1-Dimethyl-3-oxobutyl)-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide3.74 360 29

N-[3-Methoxy-4-(5-oxazolyl)phenyl]-N′-(1-methyl-1-phenylethyl)ethanediamide4.48 380 30

N-(2-Hydroxy-1,2-dimethyl-1-phenylpropyl)-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide4.29 424 31

N-[[[3-Methoxy-4-(5-oxazolyl)phenyl]amino]oxoacetyl]-2-methylalaninemethyl ester 3.68 362 32

1-[[[[3-Methoxy-4-(5-oxazolyl)phenyl]amino]oxoacetyl]amino]cyclopropanecarboxylicacidmethyl ester 2.63 360 33

N-(1-Ethynylcyclohexyl)-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide3.55 3.68 34

(R)-N-[1-(Hydroxymethyl)-1-methylpropyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]-N-methylethanediamide2.95 348 35

N-[[[3-Methoxy-4-(5-oxazolyl)phenyl]amino]oxoacetyl]-2-methylalanine2.60 348 36

N-[1,1-Dimethyl-2-oxo-2-(1-piperidinyl)ethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide2.87 415 37

N-[1,1-Dimethyl-2-(4-methyl-1-piperazinyl)-2-oxoethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide2.06 430 38

N-[1,1-Dimethyl-2-(4-morpholinyl)-2-oxoethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide2.41 417 39

4-[2-[[[[3-Methoxy-4-(5-oxazolyl)phenyl]amino]oxoacetyl]amino]-2-methyl-1-oxopropyl]-1-piperazinecarboxylicacid ethylester 2.73 488 40

N-[2-[3-(Acetylmethylamino)-1-pyrrolidinyl]-1,1-dimethyl-2-oxoethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide2.37 472 41

N-[1,1-Dimethyl-2-[methyl[2-(methylamino)ethyl]amino]-2-oxoethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide2.05 2.057 42

N-[1,1-Dimethyl-2-oxo-2-(propylamino)ethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide2.71 389 43

N-[1,1-Dimethyl-2[[2-(methylamino)ethyl]amino]-2-oxoethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide2.08 404 44

N-[1,1-Dimethyl-2-[[2-(4-morpholinyl)ethyl]amino]-2-oxoethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide2.14 460 45

N-[1,1-Dimethyl-2-oxo-2-[[3-(2-oxo-1-pyrrolidinyl)propyl]amino]ethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide2.55 472 46

N-[2-[[2-(1H-Imidazol-4-yl)ethyl]amino]-1,1-dimethyl-2-oxoethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide2.14 441 47

N-[2-[[2-(Acetylamino)ethyl]amino]-1,1-dimethyl-2-oxoethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide3.09 3.09 48

N-[2-[[2-(1H-Imidazol-1-yl)ethyl]amino]-1,1-dimethyl-2-oxoethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide2.14 441 49

N-[1,1-Dimethyl-2-oxo-2-[[2-(4-pyridinyl)ethyl]amino]ethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide2.16 452 50

N-[1,1-Dimethyl-2-oxo-2-[[(tetrahydro-2-furanyl)methyl]amino]ethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide2.63 431 51

N-[2-[(2-Methoxyethyl)amino]-1,1-dimethyl-2-oxoethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide2.47 405 52

N-[2-(Dimethylamino)-1,1-dimethyl-2-oxoethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide1.25 3.75 53

N-[2-[4-(2-Methoxyethyl)-1-piperazinyl]-1,1-dimethyl-2-oxoethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide1.22 474 54

N-[1,1-Dimethyl-2-oxo-2-(2-pyridinylamino)ethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide1.217 1.217

EXAMPLE 55 3-[[3-Methoxy-4-(5-oxazolyl)phenyl]amino]-3-oxopropanoic acidethyl ester

55 was prepared from 1D by a route analogous to that used for thepreparation of 4, replacing ethyl oxalyl chloride with ethyl malonylchloride. LC/MS: ret. time^(A)=3.169 min., MS (M+H)⁺=305.

EXAMPLE 56N-[3-Methoxy-4-(5-oxazolyl)phenyl]-N′-(3-methylphenyl)propanediamide

56A. Preparation of3-[[3-Methoxy-4-(5-oxazolyl)phenyl]amino]-3-oxopropanoic acid

56 A was prepared from 55 by a route analogous to that used for thepreparation of 5A. LC/MS: ret. time^(A)=2.611 min., MS (M+H)⁺=277.

56B. Preparation ofN-[3-Methoxy-4-(5-oxazolyl)phenyl]-N′-(3-methylphenyl)propanediamide

56 was prepared from 56A by a route analogous to that used for thepreparation of 5, replacing aniline with m-toluidine. LC/MS: ret.time^(A)=3.783 min., MS (M+H)⁺=366.

EXAMPLES 57 AND 58

Compounds 57 and 58 were prepared from 56A, by a route analogous to thatused for the preparation of 5, replacing aniline with the requiredHN₂—G². 57 and 58 have the structures as shown below and in Table 2:

TABLE 2

HPLC Ret Ex. No —G² Compound name Time^(A) (min) MS (M + H)⁺ 57

N-[3-Methoxy-4-(5-oxazolyl)phenyl]-N′-(phenyl)propanediamide 3.562 35258

(S)-[[3-[[3-[[3-Methoxy-4-(5-oxazolyl)phenyl]amino]-1,3-dioxopropyl]amino]phenyl]methyl]carbamicacidtetrahydro-3-furanyl ester 3.335 495

EXAMPLE 59 N-[3-Methoxy-4-(5-oxazolyl)phenyl]benzeneacetamide

Compound 59 was prepared from 1D by a route analogous to that used forthe preparation of 4, replacing ethyl oxalyl chloride with phenylaceticacid. LC/MS: ret. time^(A)=3.617 min., MS (M+H)⁺=309.

EXAMPLE 60 N-[3-Methoxy-4-(5-oxazolyl)phenyl]-α-oxobenzeneacetamide

Compound 60 was prepared from the product of 1D by a route analogous tothat used for the preparation of 4, replacing ethyl oxalyl chloride withbenzoylformic acid. LC/MS: ret. time^(A)=3.843 min., MS (M+H)⁺=323.

EXAMPLE 61 N-[3-Methoxy-4-(5-oxazolyl)phenyl]-1H-indole-2-carboxamide

To a solution of 1D (0.5 g, 2.63 mmol) was sequentially added anhydrousdimethylformamide (8 mL), indole-2-carboxylic acid (0.42 g, 2.63 mmol)and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.5 g, 2.63 mmol).The reaction mixture was stirred for 18 hours at room temperature,concentrated under reduced pressure and partitioned between ethylacetate (50 mL) and 1N HCl (20 mL). The ethyl acetate layer issuccessively washed with 1N NaOH (20 mL), brine (20 mL), dried oversodium sulfate and concentrated to yield 61 (0.36 g, 41%). LC/MS ret.time^(A)=4.330 min.; MS (M+H)⁺=334.

EXAMPLE 62N-[3-Methoxy-4-(5-oxazolyl)phenyl]-1-methyl-1H-indole-2-carboxamide

To a solution of 1D (30 mg, 0.158 mmol) was sequentially added1-Methylindole-2-carboxylic acid (28 mg, 0.158 mmol), BOP (100 mg, 0.237mmol), NMM (80 mg, 0.790 mmol) and anhydrous dimethylformamide (1.3 mL).The reaction mixture was stirred for 18 hours at room temperature,concentrated under reduced pressure and purified by preparative HPLC toyield 32 mg of 62. LC/MS ret time^(A)=4.177 min.; MS (M+H)⁺=348.

EXAMPLES 63–65

Compounds 63–65 were prepared from the product of 1D by a routeanalogous to that used for the preparation of 62, replacing1-Methylindole-2-carboxylic acid with the required HO(CO)—G³. Thecompounds of these examples have the structures shown in Table 3:

TABLE 3

HPLC Ret MS Ex. No —G³ Compound name time^(B) (min) (M + H)⁺ 63

N-[3-Methoxy-4-(5-oxazolyl)phenyl]-2-benzofurancarboxamide 4.023 335 64

N-[3-Methoxy-4-(5-oxazolyl)phenyl]benzo[b]thiophene-2-carboxamide 4.167351 65

N-[3-Methoxy-4-(5-oxazolyl)phenyl]-1,3-benzodioxole-5-carboxamide 3.687339

EXAMPLE 66N-[3-Methoxy-4-(5-oxazolyl)phenyl]-1-methyl-1H-pyrrole-2-carboxamide

To a mixture of 3-methoxy-4-(5-oxazoyl)aniline 1D (0.050 g, 0.263 mmol)and 1-methyl-2-pyrolecarboxylic acid (0.033 g, 0.263 mmol) in 1.0 mL ofdimethylformamide (0.050 g, 0.263 mmol) in a 2 dram rubber-linedscrewcap vial was added1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide-HCl. The reaction mixturewas placed in a Innova 2000 Platform Shaker equipped with a standardheat block and shaken at 200 rpm overnight at approximately 50° C.Aqueous acid (10%, 1 mL) was added, and the mixture was extracted threetimes with ethyl acetate. The organic layer was washed with a 1Nsolution of sodium hydroxide, washed with brine, and dried overanhydrous sodium sulfate. Concentration under reduced pressure afforded66 as a pale yellow solid. The product was 96% pure by analytical HPLCwith a ret. time=3.53 min. (Column: YMC S5 ODS 4.6×50 mm Ballistic;Solvent A=10% MeOH, 90% H₂O, 0.2% H₃PO₄; Solvent B=90% MeOH, 10% H₂O,0.2% H₃PO₄) and a LC/MS (M+H)⁺=298.23.

EXAMPLE 675-(1,1-Dimethylethyl)-N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-furancarboxamide

A mixture of 3-methoxy-4-(5-oxazoyl)aniline 1D (0.050 g, 0.263 mmol),5-tert-butyl-2-furoic acid (0.044 g, 0.263 mmol), and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide-HCl (0.050 g, 0.263 mmol)in 1.0 mL of dimethylformamide was subjected to the procedure used forthe preparation of 66 to give 52.1 mg of 67 as a yellow solid. Theproduct, 67, was 95% pure by analytical HPLC with a retention time=3.82min. (Column: YMC S5 ODS 4.6×50 mm Ballistic; Solvent A=10% MeOH, 90%H₂O, 0.2% H₃PO₄; Solvent B=90% MeOH, 10% H₂O, 0.2% H₃PO₄) and a LC/MS(M+H)⁺=341.19.

EXAMPLE 68N-[3-Methoxy-4-(5-oxazolyl)phenyl]-4,5-dimethyl-2-furancarboxamide

A mixture of 3-methoxy-4-(5-oxazoyl)aniline 1D (0.050 g, 0.263 mmol),2,3-dimethylfuran-5-carboxylic acid (0.037 g, 0.263 mmol), and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide-HCl (0.050 g, 0.263 mmol)in 1.0 mL of dimethylformamide was subjected to the procedure used forthe preparation of 66 to give 23.0 mg of 68 as a pale yellow solid. Theproduct, 68, was 95% pure by analytical HPLC with a retention time=3.79min. (Column: YMC S5 ODS 4.6×50 mm Ballistic; Solvent A=10% MeOH, 90%H₂O, 0.2% H₃PO₄; Solvent B=90% MeOH, 10% H₂O, 0.2% H₃PO₄) and a LC/MS(M+H)⁺=319.29.

EXAMPLE 69N-[3-Methoxy-4-(5-oxazolyl)phenyl]-5-methyl-2-thiophenecarboxamide

A mixture of 3-methoxy-4-(5-oxazoyl)aniline 1D (0.050 g, 0.263 mmol),5-methyl-2-thiophenecarboxylic acid (0.037 g, 0.263 mmol), and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide-HCl (0.050 g, 0.263 mmol)in 1.0 mL of dimethylformamide was subjected to the procedure used forthe preparation of 66 to give 25.8 mg of 69 as a yellow solid. Theproduct, 69, was 92% pure by analytical HPLC with a retention time=3.77min. (Column: YMC S5 ODS 4.6×50 mm Ballistic; Solvent A=10% MeOH, 90%H₂O, 0.2% H₃PO₄; Solvent B=90% MeOH, 10% H₂O, 0.2% H₃PO₄) and a LC/MS(M+H)⁺=315.17.

EXAMPLE 70N-[3-Methoxy-4-(5-oxazolyl)phenyl]-5-(2-pyridinyl)-2-thiophenecarboxamide

A mixture of 3-methoxy-4-(5-oxazoyl)aniline 1D (0.050 g, 0.263 mmol),5-(pyrid-2-yl)-thiophene-2-carboxylic acid (0.054 g, 0.263 mmol), and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide-HCl (0.050 g, 0.263 mmol)in 1.0 mL of dimethylformamide was subjected to the procedure used forthe preparation of 66 to give 4.6 mg of 70 as a yellow solid. Theproduct, 70, was 80% pure by analytical HPLC with a retention time=3.83min. (Column: YMC S5 ODS 4.6×50 mm Ballistic; Solvent A=10% MeOH, 90%H₂O, 0.2% H₃PO₄; Solvent B=90% MeOH, 10% H₂O, 0.2% H₃PO₄) and a LC/MS(M+H)⁺=378.

EXAMPLE 71N-[3-Methoxy-4-(5-oxazolyl)phenyl]-2,4-dimethyl-5-thiazolecarboxamide

A mixture of 3-methoxy-4-(5-oxazoyl)aniline 1D (0.050 g, 0.263 mmol),2,4-dimethylthiazole-5-carboxylic acid (0.041 g, 0.263 mmol), and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide-HCl (0.050 g, 0.263 mmol)in 1.0 mL of dimethylformamide was subjected to the procedure used forthe preparation of 66 to give 15.0 mg of 71 as a pale yellow solid. Theproduct, 71, was 93% pure by analytical HPLC with a retention time=3.46min. (Column: YMC S5 ODS 4.6×50 mm Ballistic; Solvent A=10% MeOH, 90%H₂O, 0.2% H₃PO₄; Solvent B=90% MeOH, 10% H₂O, 0.2% H₃PO₄) and a LC/MS(M+H)⁺=330.16.

EXAMPLE 725-Hydroxy-N-[3-methoxy-4-(5-oxazolyl)phenyl]-1H-indole-2-carboxamide

A mixture of 3-methoxy-4-(5-oxazoyl)aniline 1D (0.050 g, 0.263 mmol),5-hydroxy-2-indolecarboxylic acid (0.047 g, 0.263 mmol), and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide-HCl (0.050 g, 0.263 mmol)in 1.0 mL of dimethylformamide was subjected to the procedure used forthe preparation of 66 to give a mixture that contained ˜45% of 72. Themixture was washed with ether (2×) to give 9.2 mg of 72 as a pale yellowsolid. The product, 72, was 96% pure by analytical HPLC with a retentiontime=3.39 min. (Column: YMC S5 ODS 4.6×50 mm Ballistic; Solvent A=10%MeOH, 90% H₂O, 0.2% H₃PO₄; Solvent B=90% MeOH, 10% H₂O, 0.2% H₃PO₄) anda LC/MS (M+H)⁺=350.20.

EXAMPLE 737-Methoxy-N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-benzofurancarboxamide

A mixture of 3-methoxy-4-(5-oxazoyl)aniline 1D (0.100 g, 0.526 mmol),7-methoxy-2-benzofurancarboxylic acid (0.101 g, 0.526 mmol), and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide-HCl (0.101 g, 0.526 mmol)in 1.5 mL of dimethylformamide was subjected to the procedure used forthe preparation of 66 to give a crude product which was washed withether (2×) to give 78.0 mg of 73 as a pale yellow solid. The product,73, was 99% pure by analytical HPLC with a retention time=4.15 min.(Column: YMC S5 ODS 4.6×50 mm Ballistic; Solvent A=10% MeOH, 90% H₂O,0.2% H₃PO₄; Solvent B=90% MeOH, 10% H₂O, 0.2% H₃PO₄) and a LC/MS(M+H)⁺=365.20.

EXAMPLE 748-Hydroxy-N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-quinolinecarboxamide

A mixture of 3-methoxy-4-(5-oxazoyl)aniline 1D (0.050 g, 0.263 mmol),8-hydroxyquinoline-2-carboxylic acid (0.050 g, 0.263 mmol), and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide-HCl (0.050 g, 0.263 mmol)in 1.0 mL of dimethylformamide was subjected to the procedure used forthe preparation of 66 to give 23.0 mg of 74 as a pale yellow solid. Theproduct, 74, was 93% pure by analytical HPLC with a retention time=4.22min. (Column: YMC S5 ODS 4.6×50 mm Ballistic; Solvent A=10% MeOH, 90%H₂O, 0.2% H₃PO₄; Solvent B=90% MeOH, 10% H₂O, 0.2% H₃PO₄) and a LC/MS(M+H)⁺=362.26.

EXAMPLE 75 (E)-N-[3-Methoxy-4-(5-oxazolyl)phenyl]-3-phenyl-2-propenamide

A mixture of 3-methoxy-4-(5-oxazolyl)aniline 1D (15.0 mg, 0.0789 mmol),trans-cinnamic acid (17.5 mg, 0.118 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (18.2 mg,0.949 mmol), 4-dimethylamino pyridine (9.6 mg, 0.786 mmol), indichloromethane (2 mL) and DMF (0.5 mL) was shaken in a 16×100 mm testtube for 24 h. The reaction solution was diluted with dichloromethane (4mL), and washed successively with 1N NaOH (1 mL) and 1N HCl (1 mL).Evaporation of solvent provided the desired product 75 (18.2 mg, 72%yield). Ret. Time: 4.25 min LC/MS conditions: Column: Shimadzu 4.6×50 mmBallistic. Solvent A=10% MeOH, 90% H₂O, 0.1% TFA. Solvent B=90% MeOH,10% H₂O, 0.1% TFA and a LC/MS (M+H)⁺=321.

EXAMPLES 76–99

Compound 76 through 99 were prepared from the product 1D by a routeanalogous to that used for the preparation of 75, replacingtrans-cinnamic acid with the required HO(CO)—G⁴.

If the products carry acetic or basic moieties, the solvent wasevaporated under vacuum and products were purified by preparative HPLC.The compounds of these examples have the structures shown in Table 4:

TABLE 4

HPLC Ret MS Ex. No —G⁴ Compound name Time^(B) (min) (M + H)⁺ 76

N-[3-Methoxy-4-(5-oxazolyl)phenyl]benzamide 3.77 295 77

(E)-N-[3-Methoxy-4-(5-oxazolyl)phenyl]-3-(2-methylphenyl)-2-propenamide4.17 335 78

(E)-N-[3-Methoxy-4-(5-oxazolyl)phenyl]-3-(4-methylphenyl)-2-propenamide4.19 335 79

(E)-3-(2-Fluorophenyl)-N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-propenamide4.06 339 80

(E)-3-(3-Fluorophenyl)-N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-propenamide4.09 339 81

(E)-3-(4-Fluorophenyl)-N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-propenamide4.04 339 82

(E)-3-(2-Chlorophenyl)-N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-propenamide4.21 335 83

(E)-3-(3-Chlorophenyl)-N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-propenamide4.29 355 84

(E)-3-(4-Chlorophenyl)-N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-propenamide4.27 355 85

(E)-N-[3-Methoxy-4-(5-oxazolyl)phenyl]-3-[2-(trifluoromethyl)phenyl]-2-propenamide4.21 389 86

(E)-3-(3-Cyanophenyl)-N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-propenamide3.89 346 87

(E)-3-[4-(Acetylamino)phenyl]-N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-propenamide3.76 378 88

(E)-3-(2,3-Dimethoxyphenyl)-N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-propenamide3.96 381 89

(E)-3-(2,6-Difluorophenyl)-N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-propenamide4.11 357 90

(E)-N-[3-Methoxy-4-(5-oxazolyl)phenyl]-3-(2,3,4-trimethoxyphenyl)-2-propenamide3.97 411 91

(E)-2-Fluoro-N-[3-methoxy-4-(5-oxazolyl)phenyl]-3-phenyl-2-propenamide4.18 339 92

(E)-3-(2-Furanyl)-N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-propenamide 3.73311 93

(E)-N-[3-Methoxy-4-(5-oxazolyl)phenyl]-3-(2-thienyl)-2-propenamide 3.90327 94

(E)-N-[3-Methoxy-4-(5-oxazolyl)phenyl]-3-(3-pyridinyl)-2-propenamide2.84 322 95

(E)-N-[3-Methoxy-4-(5-oxazolyl)phenyl]-3-(4-pyridinyl)-2-propenamide2.81 322 96

(E)-N-[3-Methoxy-4-(5-oxazolyl)phenyl]-3-(1-naphthalenyl)-2-propenamide4.38 371 97

N-[3-Methoxy-4-(5-oxazolyl)phenyl]-3,4-dimethylbenzamide 4.04 334 98

N-[3-Methoxy-4-(5-oxazolyl)phenyl]-2-indolizinecarboxamide 3.78 334 99

(E)-N-[3-Methoxy-4-(5-oxazolyl)phenyl]-3-[3-methoxy-4-(phenylmethoxy)phenyl]-2-propenamide4.40 457

The materials required for the synthesis of the compounds describedabove are commercially available. The compound below (of Example 100) isuseful as an intermediate in the preparation of 9 and 58.

EXAMPLE 100 3-aminophenyl)-(+)-tetrahydrofuranylcarbamate:

100A. Preparation of 3-Aminobenzylamine

3-Cyanoaniline (0.50 g, 4.23 mmol) in 100 mL of MeOH was stirredovernight at room temperature under a H₂ environment in the presence of10% Pd/C (100 mg). The Pd/C was removed by filtration through a pad ofCelilte, and the resulting filtrate was concentrated under reducedpressure to give 0.516 g (˜100%) of 100A as a thick oil. The product wasused without any further purification.

100B. Preparation of (S)-(+)-tetrahydrofuranylchloroformate

To a solution of phosgene (8 mL of a ˜20% in toluene, 17.0 mmol) in 20mL of dichloromethane at 0° C. was added a solution of(S)-(+)-hydroxytetrahydrofuran (0.50 g, 5.67 mmol) and triethylamine(1.58 mL, 11.3 mmol) in 15 mL of dichloromethane dropwise over 20 min.The reaction mixture was stirred for 15 h at room temperature. Thesolvent was removed under reduced pressure, and the resulting residuewas dissolved in ether. The triethylamine hydrochloride salt was removedby filtration. Concentration followed by purification of the residue bysilica gel chromatography afforded 0.509 g (60%) of 100B as a clear oil.

100C. Preparation of 3-aminophenyl)-(+)-tetrahydrofuranylcarbamate

To 100A (0.509 g, 3.38 mmol) in 15 mL of dichloromethane at 0° C. wasadded a solution of the product of 100B (0.517 g, 4.23 mmol) andtriethylamine (0.94 mL, 6.76 mmol) in 15 mL of dichloromethane dropwiseover 10 min. The reaction mixture was stirred overnight at roomtemperature. The solvent was removed under reduced pressure, and theresidue was dissolved in ether. The solid triethylamine hydrochloridesalt was removed by filtration. Concentration followed by purificationof the residue by silica gel chromatography afforded 0.508 g (64%) of100 as a clear oil. LC/MS: ret. time^(A)=1.07 min.; MS (M+H)⁺=237.

Although the present invention has been described in some detail by wayof illustration and example for purposes of clarity and understanding,it will be apparent that certain changes and modifications may bepracticed within the scope of the appended claims.

1. A compound or pharmaceutically acceptable salt thereof having theformula,

wherein R¹ is selected from the group consisting of OCF₃ andC₁–C₄alkoxy; R² and R⁵ are each hydrogen; R⁶ is selected from H, C₁–C₈alkyl, C₃–C₆ alkenyl, C₃–C₆ alkynyl, C₃–C₁₀ cycloalkyl(C₀–C₄ alkyl)-,aryl(C₀–C₄ alkyl)-, and heterocyclic (C₀–C₄ alkyl)-, wherein said arylor heterocyclic groups are substituted with 0–2 substituentsindependently selected from C₁–C₄ alkyl, C₁–C₄ alkoxy, hydroxy C₀–C₄alkyl, oxo, F, Cl, Br, CF₃, NO₂, CN, OCF₃, NH₂, NHR⁷, NR⁷R⁸, SR⁷,S(O)R⁷, SO₂R⁷, SO₂NR⁷R₈, CO₂H, CO₂, R⁷, and CONR⁷R⁸; R⁷ is selected fromhydrogen and C₁–C₈ alkyl; R⁸ is selected from H, C₁–C₈ alkyl, C3–C₆alkenyl, C₃–C₆ alkynyl, C₃–C₁₀ cycloalkyl (C₀–C₄ alkyl)-, C₁–C₆alkylcarbonyl, C₃–C₇, cycloalkyl(C₀–C₅ alkyl)carbonyl, C₁–C₆alkoxycarbonyl, C₃–C₇, cycloalkyl(C₀–C₅ alkoxy)carbonyl, aryl(C₁–C₅alkoxy)carbonyl, arylsulfonyl, aryl(C₀–C₄ alkyl)-, heterocyclic(C₁–C₅alkoxy)carbonyl, heterocyclic sulfonyl and heterocyclic (C₀–C₄ alkyl)-,wherein said aryl or heterocyclic groups are substituted with 0–2substituents independently selected from the group consisting of C₁–C₄alkyl, C₁–C₄ alkoxy, F, Cl, Br, CF₃, CN, and NO₂; or R⁶ and R⁷, or R⁶and R⁸, when both substituents are on the same nitrogen atom, do or donot form, with the nitrogen atom to which they are attached, aheterocycle selected from 1-aziridinyl, 1-azetidinyl, 1-piperidinyl,1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and1-piperazinyl, said heterocycle is unsubstituted or substituted with 0–3groups selected from oxo, C₁–C₆ alkyl, C₃–C₇ cycloalkyl(C₀–C₄ alkyl)-,C₁–C₆ alkylcarbonyl, C₃–C₇ cycloalkyl(C₀–C₅ alkyl)carbonyl, C₁–C₆alkoxycarbonyl, C₃–C₇ cycloalkyl(C₀–C₅ alkoxy)carbonyl, aryl(C₀–C₅alkyl), heterocyclic(C₀–C₅ alkyl), aryl(C₁–C₅ alkoxy)carbonyl,heterocyclic(C₁–C₅ alkoxy)carbonyl, C₁–C₆ alkylsulfonyl, arylsulfonyl,and heterocyclicsulfonyl, wherein said aryl or heterocyclic groups aresubstituted with 0–2 substituents independently selected from C₁–C₄alkyl, C₁–C₄ alkoxy, F, Cl, Br, CF₃, CN, and NO₂; K is selected from—C(═O)—and —CHR⁹—; L is selected from a single bond, —C(═O), —CR¹⁰R¹¹—,—CR¹⁰R¹¹—(C═O)—, —HR¹⁵C—CHR¹⁶—, and —R¹⁵C═CR¹⁶; X is heterocyclic(C₀–C₄alkyl)-, wherein the heterocyclic group is substituted by 0–3substituents independently selected from R¹⁴; R⁹ is selected from H,C₁–C₈ alkyl, C₃–C₆alkenyl, C₃–C₁₀ cycloalkyl(C₀–C₄ alkyl)-, aryl(C₀–C₄alkyl)-, and heterocyclic(C₀–C₄ alkyl)-, wherein said aryl orheterocyclic groups are substituted with 0–2 substituents independentlyselected from C₁–C₄ alkyl, C₁–C₄ alkoxy, F, Cl, Br, CF₃, and NO₂; R¹⁰ isselected from H, F, Cl, Br, C₁–C₆ alkoxy, C₁–C₈ alkyl, C₃–C₆ alkenyl,C₃–C₁₀ cycloalkyl(C₀–C₄ alkyl)-, aryl(C₀–C₄ alkyl)-, andheterocyclic(C₀–C₄ alkyl)-, wherein said aryl or heterocyclic groups aresubstituted with 0–2 substituents independently selected from C₁–C₄alkyl, C₁–C₄ alkoxy, F, Cl, Br, CF₃, CN, and NO₂; R¹¹ is selected fromH, F, Cl, Br, OMe, C₁–C₈ alkyl, C₃–C₆ alkenyl, C₃–C₁₀ cycloalkyl(C₀–C₄alkyl)-, aryl(C₀–C₄ alkyl)-, and heterocyclic(C₀–C₄ alkyl)-, whereinsaid aryl or heterocyclic groups are substituted with 0–2 substituentsindependently selected from C₁–C₄ alkyl, C₁–C₄ alkoxy, F, Cl, Br, CF₃,CN, and NO₂; or R¹⁰ and R¹¹, when on the same carbon atom, do or do notform, with the carbon atoms to which they are attached, a 3–7 memberedcarbocyclic or 3–7 membered heterocyclic non-aromatic ring system, saidcarbocyclic or heterocyclic ring is unsubstituted or substituted with0–2 substituents independently selected from C₁–C₄ alkyl, C₁–C₄ alkoxy,hydroxy C₀–C₄ alkyl, oxo, F, Cl, Br, CF₃, and NO₂; R¹⁴ is selected fromH, C₁–C₁₀ alkyl, NO₂, CF₃, CN, F, Cl, Br, C₁–C₁₀ alkylcarbonyl,haloalkyl, haloalkoxy, OH, NR⁶R⁷(C₀–C₄ alkyl)-, R⁶ C(═O)O(C₀–C₄ alkyl)-,R⁶OC(═O)O (C₀–C₄ alkyl)-, R ⁶O (C₀–C₄ alkyl), R⁶R⁷ NC(═O) O(C₀–C₄alkyl)-, R⁶R⁷ NC(═O) (C₀–C₄ alkyl)-, R^(6 O(CR) ¹⁰R¹¹)₂₋₆R⁶NC(═O) (C₀–C₄alkyl)-, R⁶R⁷N(CR¹⁰R¹¹)₂₋₆R⁶NC(═O) (C₀–C₄ alkyl)-, R⁶O₂, C(CH₂)₁₋₄O(C₀–C₄ alkyl)-, R⁶OOC(C₁–C₄ alkoxy), —R⁶OOC (C₀–C₄ alkyl)-,R⁶C(═O)(C₀–C₄ alkyl)-, R⁶C(═O)NR⁷(C₀–C₄ alkyl)-, R⁶OC(═O)NR⁷(C₀–C₄alkyl)-, R⁶OC(═NCN)NR⁷(C₀–C₄ alkyl)-, R⁶R⁷NC(═O)NR⁸(C₀–C₄ alkyl)-,R⁶OC(═NC) NR⁷(C₀–C₄ alkyl)-, R⁶(CR¹⁰R¹¹)₁₋₄NR⁷C═O—, R⁶O(CR¹⁰R¹¹)₁₋₄O═CR⁷N—, NR⁶R⁷(CR¹⁰R¹¹)₁₋₄C═O R⁷N—, R⁶O(CR¹⁰R¹¹)₂₋₄R⁷N—,R⁶O₂C(CR¹⁰R¹¹)₁₋₄R⁷N, R⁶R⁷N (CR¹⁰R¹¹)₂₋₄R⁷N—,R⁶R⁷NC(═NCN)NR⁷(C₀–C₄alkyl)-, R⁶R⁷NC(═C(H)(NO₂))NR⁷(C₀–C₄ alkyl)-, R⁷R⁸NC(═NR⁷) NR⁷(C₀–C₄ alkyl)-, R⁶R⁷N SO₂NR⁸(C₀–C₄ alkyl)-, R⁶SO₂NR⁷(C₀–C₄alkyl)-, R⁶R⁷N(C₁–C₄) CO—, R⁶R⁷N(C₂–C₆ alkyl)O—,R⁶CO(CR¹⁰R¹¹)₀₋₂R⁷N(O₂)S(C₀–C₄ alkyl), R⁶(O₂)S R⁷NC(═O) (C₀–C₄ alkyl)-,R⁶S(C₀–C₄ alkyl)-, R⁶S(═O) (C₀–C₄ alkyl)-, R⁶SO₂(C₀–C₄ alkyl)-,SO₂NR⁶R⁷, SiMe₃ , R⁶R⁷N(C₂–C₄ alkyl)-, R⁶R⁷N(C₂–C₄ alkoxy)-, HSO₃,HONH—, R⁶ONH—, R⁸R⁷NNR⁶—, HO(COR⁶)N—, HO(R⁶O₂C)N, C₂–C₆ alkenyl, C₃–C₁₀cycloalkyl, C₃–C₁₀ cycloalkylmethyl, aryl(C₀–C₄alkyl)-,heteroaryl(C₀–C₄alkyl)-, aryl(C₀–C₄alkyl)O—, andheteroaryl(C₀–C₄alkyl)O—, wherein said aryl groups are substituted with0–2 substituents independently selected from C₁–C₄ alkyl, C₁–C₄ alkoxy,R, Cl, Br, CF₃, and NO₂; R¹⁵ is selected from H, halo, cyano, C₁–C₈alkyl, C₃–C₆ alkenyl, and C₃–C_(10 cycloalkyl(C) ₀–C₄ alkyl)-,aryl(C₀–C₄ alkyl)-, and heterocyclic(C₀–C₄ alkyl)-, wherein said aryl orheterocyclic groups are substituted with 0–2 substituents independentlyselected from R¹⁴; and R¹⁶ is selected from H, halo, cyano, C₁–C₈ alkyl,C₃–C₆ alkenyl, C₃–C₁₀ cycloalkyl(C₀–C₄ alkyl)-, aryl(C₀–C₄ alkyl)-, andheterocyclic(C₀–C₄ alkyl)-, wherein said aryl or heterocyclic groups aresubstituted with 0–2 substituents independently selected from R¹⁴; orwhen R¹⁵ and R¹⁶ are on adjacent carbon atoms, or when R¹⁵ and R¹⁶ areoriented on the same side of the double bond, as depicted in thefollowing structure (III)

R¹⁵ and R¹⁶ do or do not form, with the carbon atoms to which they areattached,a 3–7 membered carbocyclic aromatic or nonaromatic ring system,or a 3–7 membered heterocyclic aromatic or nonaromatic ring system, saidcarbocyclic or heterocyclic ring is unsubstituted or substituted with0–2 substituents independently selected from C₁–C₄ alkyl, C₁–C₄ alkoxy,F, Cl, Br, CF₃,and NO₂.
 2. The compound or a pharmaceutically acceptablesalt thereof of claim 1 wherein: ps K is —C═O—and L is —═O—.
 3. Thecompound or a pharmaceutically acceptable salt thereof of claim 2 havingthe formula,

wherein: R⁷ is hydrogen; and R¹ is methoxy.
 4. The compound or apharmaceutically acceptable salt thereof of claim 1 wherein: K is —═Oand L is a single bond.
 5. The compound or a pharmaceutically acceptablesalt thereof of claim 4 having the formula,


6. A compound or a pharmaceutically acceptable salt thereof of claim 1wherein: K is —C═O—and L is —R¹⁵C═CR¹⁶—.
 7. A compound or apharmaceutically acceptable salt thereof of claim 6 having the formula,


8. A compound or a pharmaceutically acceptable salt thereof of claim 1wherein: K is —C═O—and L is CR¹⁰R¹¹—(C═O)—.
 9. A compound or apharmaceutically acceptable salt thereof of claim 8 having the formula,


10. A compound or a pharmaceutically acceptable salt thereof, whereinsaid compound is selected from:N-[3-Methoxy-4-(5-oxazolyl)phenyl]-1H-indole-2-carboxamideN-[3-Methoxy-4-(5-oxazolyl)phenyl]-1-methyl-1H-indole-2-carboxamideN-[3-Methoxy-4-(5-oxazolyl)phenyl]-2-benzofurancarboxamideN-[3-Methoxy-4-(5-oxazolyl)phenyl]benzo[b]thiophene-2-carboxamideN-[3-Methoxy-4-(5-oxazolyl)phenyl]-1,3-benzodioxole-5-carboxamideN-[3-Methoxy-4-(5-oxazolyl)phenyl]-1-methyl-1H-pyrrole-2-carboxamide5-(1,1-Dimethylethyl)-N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-furancarboxamideN-[3-Methoxy-4-(5-oxazolyl)phenyl]-4,5-dimethyl-2-furancarboxamideN-[3-Methoxy-4-(5-oxazolyl)phenyl]-5-methyl-2-thiophenecarboxamideN-[3-Methoxy-4-(5-oxazolyl)phenyl]-5-(2-pyridinyl)-2-thiophenecarboxamideN-[3-Methoxy-4-(5-oxazolyl)phenyl]-2,4-dimethyl-5-thiazolecarboxamide5-Hydroxy-N-[3-methoxy-4-(5-oxazolyl)phenyl]-1H-indole-2-carboxamide7-Methoxy-N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-benzofurancarboxamide8-Hydroxy-N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-quinolinecarboxamide(E)-3-(2-Furanyl)-N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-propenamide(E)-N-[3-Methoxy-4-(5-oxazolyl)phenyl]-3-(2-thienyl)-2-propenamide(E)-N-[3-Methoxy-4-(5-oxazolyl)phenyl]-3-(3-pyridinyl)-2-propenamide(E)-N-[3-Methoxy-4-(5-oxazolyl)phenyl]-3-(4-pyridinyl)-2-propenamide andN-[3-Methoxy-4-(5-oxazolyl)phenyl]-2-indolizinecarboxamide.
 11. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier, adjuvant or vehicle and at least one compound of claim 1, or apharmaceutically acceptable salt thereof, in an amount effectivetherefor.
 12. A method for the treatment of an IMPDH-associated disorderwherein the disorder is selected from transplant rejection, rheumatoidarthritis, inflammatory bowel disease, hepatitis B, hepatitis C, herpessimplex type I, and herpes simplex type II, comprising the steps ofadministering to a subject in need thereof an amount effective thereforof at least one compound of claim 1 or a pharmaceutically acceptablesalt thereof.